Clinical trial NCT02363998
Conditions: Opioid Withdrawal
Keywords: detoxification agonist taper methadone step down buprenorphine step down opioid withdrawal syndrome
Sponsor: USWM, LLC (dba US WorldMeds)
Start date: 2015-02-01; Completion date: 2015-10-01
Enrollment: 286 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this Phase 3 open-label treatment study is to evaluate the safety and effectiveness of lofexidine at a clinically relevant dose to alleviate symptoms of acute withdrawal from any opioid, including methadone and buprenorphine. This study will take place in a variety of clinical scenarios, both in-clinic and outpatient settings.

Detailed description:
Eligible subjects (person seeking treatment for partial or total opioid withdrawal) enrolled in this study are required to take lofexidine for a minimum of 7 days.

Arms: arm 1: During this open-label study, subjects will be given the option to receive lofexidine tablets for 7 days and up to 14 days if requested.
Interventions: intervention 1: Lofexidine
Intervention descriptions: intervention 1: All enrolled subjects will take lofexidine orally for 7 days, starting on Day 1 at a dose of 3.2 mg per day (0.8 mg QID), with lowering of the dose allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the subject's individual treatment goal and response per clinical judgment of the Principal Investigator.

Protocol documents:
ICF_002.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
SUBJECT INFORMATION AND CONSENT FORM AND 
AUTHORIZATION TO USE AND DISCLOSE PERSONAL HEALTH 
INFORMATION IN CLINICAL RESEARCH 
PROTOCOL NUMBER: USWM-LX1-3003-2
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
TITLE: 
A Phase 3, Open-Label, Safety Study of Lofexidine 
DOCUMENT DATE: 16JAN2015 
NDA NUMBER: 209229 
NCT NUMBER: NCT02363998 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 1 of 13 
 
 
SUBJECT INFORMATION AND CONSENT FORM AND AUTHORIZATION TO USE AND 
DISCLOSE PERSONAL HEALTH INFORMATION IN CLINICAL RESEARCH 
 
 
A Phase 3, Open-Label, Safety Study of Lofexidine 
 
Sponsor: 
 
 
 
US WorldMeds, LLC 
 
Protocol Number:  
 
USWM-LX1-3003-2 
 
 
 
January 16, 2015 (inclusive of Amendment No. 1) 
 
Principal Investigator: 
 
 
 
Daytime telephone numbers: 
 
24-Hour Telephone: 
 
 
 
 
PURPOSE OF THE SUBJECT INFORMATION AND CONSENT FORM 
This Subject Information and Consent Form may contain words you do not understand.  Please ask the 
study doctor or the study staff to explain any words or procedures that you do not clearly understand. 
The purpose of this form is to give you information about the research study and, if signed, will 
give your permission to take part in the study.  The form describes the purpose, procedures, benefits, 
risks, discomforts, and precautions of the research study.  You should take part in this study only if 
you want to do so.  You may refuse to take part or withdraw from this study at any time without penalty 
or loss of benefits to which you are otherwise entitled.  Please read this Subject Information and 
Consent Form and ask as many questions as needed.  You should not sign this form if you have 
any questions that have not been answered to your satisfaction.   
PURPOSE AND DESCRIPTION OF THE RESEARCH STUDY 
You are being asked to take part in a research study of a drug called lofexidine to see if it is useful 
and safe in reducing opioid withdrawal symptoms in people who are addicted to opioids (for 
example, heroin and morphine).  Lofexidine is a non-addictive drug used in England to decrease 
symptoms of opioid withdrawal.  The Food and Drug Administration (FDA) has not yet approved 
lofexidine in the United States.  Because lofexidine is not FDA approved for treating opioid 
withdrawal, it is called an investigational drug.  In this study we are primarily studying the 3.2 mg 
dosage strength of lofexidine provided in tablet form for oral administration (by mouth).  If you have 
difficulty tolerating the 3.2 mg dose, you may receive a lower dose of lofexidine (2.4 mg). 
You are being considered for participation in this research study because you are addicted to 
opioids and are seeking treatment for your addiction or you and your doctor wish to change the 
opioid treatment you are currently receiving.  About 250 to 500 subjects at about 20 study sites 
across the United States will participate in this study.  It will take about 4 to 10 months to enroll up 
to 500 subjects.   


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 2 of 13 
If you participate in this study, you will be required to remain in a clinic setting (hospital, treatment 
facility, clinic, or clinic-associated housing facility) for the first 3 days of the study where you will 
take lofexidine 4 times each day (8 AM, 1 PM, 6 PM, and 11 PM).  Over the next 4 days (Days 4-7), 
you will either remain in the clinic setting for treatment with lofexidine or be discharged and treated 
with lofexidine outside of the clinic (as an outpatient), as determined by you and your study doctor.  
You may receive lofexidine treatment up to 7 additional days (outpatient only, Days 8-14) if your 
study doctor decides lofexidine is needed for you to control your withdrawal symptoms.  The study 
will take place over a maximum of 23 days and the total number of days you may receive lofexidine 
is 14 days. 
STUDY PROCEDURES 
Screening 
If you agree to take part in this study, you will first review the consent form and HIPAA (Health 
Insurance Portability and Accountability Act) document with study staff.  You must sign the consent and 
HIPAA forms before any study-related procedures can be performed, as described below.  Screening 
procedures and/or assessments may require up to 3 clinic visits and the information collected is used to 
determine if you are eligible to enter the study.  If you are not eligible, you will be assisted in finding 
other substance abuse treatment programs in your geographic area, if you so desire, at your own 
cost or through your regular health care provider. 
• 
Study staff will ask you a series of questions to check your eligibility to participate against a 
list of inclusion and exclusion criteria provided by the sponsor. 
• 
Study staff will collect your medical, smoking, and alcohol history and demographic information. 
• 
Study staff will collect your prior medication history (over last 30 days).  It is important to tell 
the study staff all of the medications you are taking, including prescription, nonprescription 
(over-the-counter medications), opioids of abuse, and herbal preparations. 
• 
A study doctor or designee will complete the Mini International Neuropsychiatric Interview 
(M.I.N.I.) questionnaire to document your addiction to opioids and any past or current 
nervous system diseases or mental health illnesses. 
• 
A study doctor or designee will perform a complete physical examination and measure your 
blood pressure and pulse (while sitting or laying down and standing), respiration rate 
(breaths per minute) and temperature. Your height and weight will be collected also. 
• 
You will have a blood sample drawn (about ½ ounce or 3 teaspoonfuls).  This blood will 
show the study doctor how various systems in your body, for example how your liver and 
kidneys, are working.  Some people who have abused opioids for a long time do not have 
"good veins" even for a single blood draw.  If blood cannot be obtained for the required 
medical tests, you will not be eligible for participation in this study. 
• 
You will have to provide an observed urine sample.  Some of this urine will be tested for 
drugs (like heroin and methadone), some will be used to see how your kidneys and other 
parts of your body are working, and some used for pregnancy testing as described 
immediately below. 
• 
If you are female and capable of becoming pregnant, some of the urine collected will be 
used for pregnancy testing.  The result must be negative to participate in the study.  If you 
are able to become pregnant, you must agree to using birth control for the entire duration of 
this research study.  Your study doctor will discuss acceptable forms of birth control. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 3 of 13 
• 
You will be tested for infectious diseases (hepatitis, syphilis, and tuberculosis) and given the 
results of these tests.  If your tuberculosis skin test is positive, you will have a chest x-ray 
performed to assess active tuberculosis.  You will also have a chest x-ray performed if you have 
previously been positive for tuberculosis.  You will not be eligible for study participation if your 
syphilis or tuberculosis tests are positive, and you will be referred, at your own cost, for 
appropriate follow-up and/or treatment. You may still be eligible for study participation if you 
have a positive result for hepatitis but no active liver disease otherwise.  The study doctor 
should know if you have been exposed to a hepatitis virus in the past.  A positive result from 
these tests will be reported to the local health department as required by state law.  The results 
from these tests are confidential and results will not be shared outside of this study except as 
required by state law.  While expected to be confidential, these results, if disclosed, may affect 
your employment or health insurance options. 
• 
You will have an electrocardiogram (ECG) performed to measure the electrical activity of 
your heart.  This will be done 2 times (8 AM and 11:30 AM) on one day during the 
screening period. 
• 
You will have a short-term (within the 14-day study period) withdrawal treatment goal 
defined, for example, abrupt and total withdrawal from heroin, total withdrawal from heroin 
with assistance with methadone. 
Mandatory In-clinic Treatment (Days 1-3) 
For the in-clinic part of this study, you will be required to stay in a unit (hospital, treatment facility, clinic, 
or clinic-associated housing facility), which may or may not be locked, with or without visitors, and you 
will be required to follow all rules and regulations of the unit.  You will be allowed to eat only the food 
served at the unit (no carry-out).  If you are eligible to participate, you will be admitted in time to have 
the following assessments completed before you receive your first dose of lofexidine at 8 AM on Day 1: 
• 
You will complete the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) questionnaire 
to document the severity of your withdrawal symptoms. 
• 
A study doctor or designee will complete the Clinical Opiate Withdrawal Scale (COWS) 
questionnaire to document the severity of 11 common opioid withdrawal signs and symptoms. 
• 
A study doctor or designee will complete the Columbia-Suicide Severity Rating Scale(C-SSRS) 
(baseline version) to document any suicidal thoughts or behaviors over your lifetime. 
• 
A study doctor or designee will perform a physical exam to see if you have any new medical 
problems since your screening visit. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down; and standing), respiration rate (breaths per minute) and temperature. 
• 
You will have a urine drug screen performed. 
• 
If you are a female capable of becoming pregnant, you will have a urine pregnancy test 
performed. 
• 
Study staff will ask about any medications you have taken since your screening visit. 
• 
You will have an ECG performed to measure the electrical activity of your heart before the 8 AM 
dose. 
Lofexidine treatment will start after the above procedures confirm you are eligible to participate in 
this study.  You will be given 4 tablets of lofexidine 4 times a day (8 AM, 1 PM, 6 PM, and 11 PM) 
for 3 days.  In all, you will receive 16 tablets each day while in the unit. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 4 of 13 
Medicines other than those your doctor gives you are not permitted.  Allowed medicines your doctor 
may give you include nicotine replacement therapy (patch, inhaler, gum, nasal spray) and other 
medications to treat complaints such as diarrhea; constipation; indigestion and nausea; headache, 
muscle aches, and other discomforts; cough; and insomnia. 
You may be allowed to smoke in the unit, if smoking is permitted in the unit.  If you usually smoke 
tobacco products, the doctors will offer and encourage you to use nicotine replacement medications 
(for example, nicotine patch, gum, inhaler, or nasal spray) while you are in the unit to treat your 
nicotine withdrawal symptoms and to make it easier for you not to smoke.  If smoking is allowed, 
smoking breaks outside the in-clinic unit will be constantly observed and supervised. 
The following assessments will be completed every day (unless otherwise specified) while you are 
in the unit on Days 1-3: 
• 
You will complete the SOWS-Gossop questionnaire each day (3.5 hours after the first dose) to 
document the severity of your withdrawal symptoms. 
• 
A study doctor or designee will complete the COWS questionnaire each day (3.5 hours after the 
first dose) to document the severity of 11 common opioid withdrawal signs and symptoms. 
• 
A study doctor or designee will complete the C-SSRS (since last visit version) each day 
(3.5 hours after the first dose) to document any suicidal thoughts or behaviors since the last 
time the scale was completed.  
• 
A study doctor or designee will assess whether you have completed your pre-defined 
withdrawal treatment goal. 
• 
Study staff will document any medications you have taken. 
• 
Study staff will monitor you continuously for side effects. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down; and standing, if able) before every dose and 3.5 hours after the 8 AM, 1 PM, and 6 PM 
doses.  Respiration rate and temperature will be measured before the 8 AM dose only. 
• 
A study doctor or designee will perform a complete physical exam 3 to 4 hours after dosing on 
Day 1 and as clinically needed to monitor your health. 
• 
You will have an ECG performed 3.5 hours after the first dose on Day 1. 
• 
You will have a fingerprick blood sample collected at the same time the ECG is performed on 
Day 1 (3.5 hours after the first dose). 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected if clinically 
needed to monitor your health. 
• 
You will have a urine drug screen performed every day. 
In-clinic or Outpatient Treatment (Days 4-7) 
As determined by you and your study doctor, you may continue to receive lofexidine treatment in a 
clinic setting or you can be treated outside of the clinic (outpatient) for the remaining 4 days of 
mandatory lofexidine treatment (Days 4-7).  If you receive lofexidine treatment on an outpatient 
basis, you will be required to return to the clinic daily before a scheduled dose for the clinical 
assessments listed below. 
The following assessments and procedures will be completed every day (unless otherwise 
specified) on Days 4-7: 
• 
You will take study medication 4 times a day at 8 AM, 1 PM, 6 PM, and 11 PM. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 5 of 13 
• 
You will complete the SOWS-Gossop questionnaire 3.5 hours after the first daily dose during 
in-clinic treatment to document the severity of your withdrawal symptoms; if outpatient, this will 
be completed once daily before dosing. 
• 
A study doctor or designee will complete the COWS questionnaire 3.5 hours after the first daily 
dose during in-clinic treatment to document the severity of 11 common opioid withdrawal signs 
and symptoms; if outpatient, this will be completed once daily before dosing. 
• 
A study doctor or designee will complete the C-SSRS (since last visit version) 3.5 hours after 
the first daily dose during in-clinic treatment to document any suicidal thoughts or behaviors 
since the last time the scale was completed; if outpatient, this will be completed once daily 
before dosing.  
• 
A study doctor or designee will assess whether you have completed your pre-defined 
withdrawal treatment goal. 
• 
Study staff will document any medications you have taken. 
• 
Study staff will monitor you continuously for side effects during in-clinic treatment.  If outpatient, 
you will be asked about any side effects you may have experienced since your last visit. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down; and standing, if able) during in-clinic treatment before every dose and 3.5 hours after the 
8 AM, 1 PM, and 6 PM doses.  Respiration rate and temperature will be measured before 8 AM 
dose only. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down; and standing, if able) during outpatient treatment at least once daily before dosing and 
3.5 hours after dosing.  If you cannot stay in the clinic for the 3.5-hour measurements, you will 
given a portable blood pressure machine to measure your blood pressure and pulse at this 
required time point.  You will also be given a paper diary to record these values. 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected if clinically 
needed to monitor your health. 
• 
A study doctor or designee will perform a complete physical exam if clinically needed to monitor 
your health. 
• 
You will have a urine drug screen performed every day during in-clinic treatment and every day 
during outpatient treatment. 
• 
You will have a fingerprick blood sample collected each day during outpatient treatment. 
• 
If outpatient, you will be given a paper diary to record the time of dosing for each of the 4 
required daily doses; to record blood pressure and pulse if not recorded during the in-clinic visit; 
and to record any symptoms of hypotension (low blood pressure) or bradycardia (low pulse), as 
listed in the paper diary. 
• 
If outpatient, you will need to return the dispensed study medication bottles and study diary 
every day when you return to the clinic so the study staff can account for all study medication. 
After 7 days of lofexidine treatment, your study doctor will decide if you still need lofexidine to 
control your withdrawal symptoms.  If not, you will be discharged from the study after at least 
one dose on Day 7 and all end-of-study procedures have been completed.  If your study doctor 
decides you need to continue lofexidine treatment, you may receive lofexidine treatment on an 
outpatient basis only (see below). 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 6 of 13 
Outpatient Only Treatment (Days 8-14) 
As determined by your study doctor, you may continue lofexidine treatment on an outpatient basis 
only for up to an additional 7 days to control your withdrawal symptoms.  Lofexidine dosing may be 
stopped at any time during Days 8-14.  You will be required to return to the clinic daily before a 
scheduled dose for the clinical assessments listed below. 
The following assessments and procedures will be completed every day (unless otherwise 
specified) on Days 8-14: 
• 
You will complete the SOWS-Gossop before dosing. 
• 
A study doctor or designee will complete the COWS questionnaire before dosing. 
• 
A study doctor or designee will complete the C-SSRS (since last visit version) before dosing.  
• 
A study doctor or designee will assess whether you have completed your pre-defined 
withdrawal treatment goal. 
• 
Study staff will document any medications you have taken. 
• 
Study staff will ask you about any side effects you may have experienced since your last visit. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down; and standing, if able) at least once daily before dosing and 3.5 hours after dosing on 
Days 8-13 and once before any dose on Day 14.  If you cannot stay in the clinic for the 3.5-hour 
measurements, you will given a portable blood pressure machine to measure your blood 
pressure and pulse at this required time point.  You will also be given a paper diary to record 
these values.   
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected if clinically 
needed to monitor your health. 
• 
A study doctor or designee will perform a complete physical exam if clinically needed to monitor 
your health. 
• 
You will have a urine drug screen performed every day. 
• 
You will have a fingerprick blood sample collected every day. 
• 
You will be given a paper diary to record the time of dosing for each of the 4 required daily 
doses; to record blood pressure and pulse if not recorded during the in-clinic visit; and to record 
any symptoms of hypotension (low blood pressure) or bradycardia (low pulse), as listed in the 
paper diary. 
• 
You will need to return the dispensed study medication bottles and study diary every day when 
you return to the clinic so the study staff can account for all study medication. 
Study Discontinuation/End of Study 
When you complete or if you are removed from the study for any reason, you will have the following 
assessments completed after your last dose of study medication: 
• 
A study doctor or designee will complete the COWS and C-SSRS questionnaires. 
• 
A study doctor or designee will assess whether you have completed your pre-defined 
withdrawal treatment goal. 
• 
You will complete the SOWS-Gossop. 
• 
Study staff will ask about any medications you have taken and any side effects you may 
have experienced since your last visit. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 7 of 13 
• 
You will have an ECG performed before your last dose and after dosing. 
• 
A study doctor or designee will perform a complete physical examination and measure your 
blood pressure and pulse (while sitting or laying down; and standing, if able), respiration 
rate, temperature, and weight. 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected to 
document your overall health. 
• 
If you are a female of childbearing potential (capable of being pregnant), you will have a 
urine pregnancy test. 
• 
You will have a urine drug screen performed. 
• 
If you are being treated as an outpatient, you will need to return the dispensed study 
medication bottle when you return to the clinic so the study staff can account for all study 
medication. 
Study staff will contact you by telephone 30 days after your last dose of study medication to ask you 
about your current treatment status (for example, current psychosocial treatment, relapse, or 
successful entry into another substance abuse treatment program) and any side effects you may 
have experienced since your last visit. 
SUBJECT OBLIGATIONS 
If you are a female and capable of becoming pregnant, you must use birth control during your 
participation in the study.  You can discuss birth control options with your study doctor. 
You will be allowed to take medications during the study, as necessary, for example, nicotine 
replacement therapy (patch, inhaler, gum, nasal spray) and medications to treat complaints such as 
diarrhea (e.g., Pepto-Bismol, Imodium); constipation (e.g., dioctyl sodium sulfosuccinate and psyllium 
hydrocolloid suspension); indigestion and nausea (e.g., Alumina, Magnesia, and Simethicone); 
headache, muscle aches, and other discomforts (e.g., Tylenol, Advil); cough (e.g., guaifenesin); and 
insomnia (e.g., zolpidem, trazadone).  It is very important that you discuss with the study doctor 
before you begin taking any other prescription or nonprescription (over-the-counter) medications, 
or herbal preparations to make sure they are acceptable to take with the study drug.  Some drugs may 
have dangerous interactions with lofexidine, as described further in the section immediately below. 
RISKS OR DISCOMFORTS 
Lofexidine, as an investigational drug, may involve some risks to you that are currently unknown.  
Your opioid withdrawal symptoms may improve, not change, or may worsen if you take part in this 
research study. 
There is a chance that you may experience opioid withdrawal symptoms during the study including 
nausea, vomiting, diarrhea, muscle pain, abdominal discomfort, sweating, runny nose, watery eyes, 
restlessness, tremors, chills, increased heart rate and blood pressure, and agitation. 
You may experience some side effects from the study drug.  Lofexidine, at the doses planned in this 
study, may cause a decrease in blood pressure and pulse and cause dizziness, especially when you 
stand up too quickly.  After the study drug is discontinued, you may experience a temporary increase 
in blood pressure.   
You may also experience drowsiness and/or dry mouth, nose, or throat while taking lofexidine.  Other 
rare side effects of lofexidine that have been reported by less than 5% of subjects in other completed 
trials, which are listed in the Investigator's Brochure for lofexidine, may include trouble breathing, very 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 8 of 13 
slow heart rate, severe skin rash, faintness, unusual tiredness or extreme weakness, constipation, or 
loss of appetite.  There are also some reports of the QTc interval of the heart being too long in people 
taking lofexidine.  The QTc interval is a measurement on an ECG reading that shows the electrical 
activity in the heart’s lower chambers, the ventricles.  When the careful timing of the heart’s patterns 
are upset or disrupted and the QTc interval is longer than usual; it can lead to fainting, heart attack, or 
sudden death.  There was one report of a person who experienced Torsades de Points, a potentially 
fatal abnormal heart rhythm (although this patient recovered and it was not clear if lofexidine was 
responsible for the event).  Torsades de Pointes is an irregular heartbeat caused by the heart’s lower 
chambers beating faster than usual, causing less blood to pump out of the heart, which leads to 
sudden fainting.  If the episode is short, the heart can correct itself on its own.  If an episode of 
Torsades de Points persists, however, it can lead to an irregular heartbeat known as ventricular 
fibrillation (a condition causing the lower chambers of the heart to beat so fast that the heart shakes 
and stops pumping blood) and possibly death. 
You should be aware that you will probably be more sensitive to the effects of heroin and other 
opioids after you complete this study.  You should be extremely careful after you leave the study, if 
you decide to use opioids again.  Any opioid, even at doses you took in the past, could cause an 
overdose, severe medical problems, or even death. 
Risks associated with drawing blood from your arm or by finger stick include pain, bruising, 
lightheadedness and, on rare occasions, infection.  Precautions will be taken to minimize these risks.  
The total amount of blood that you will be asked to give during the study is about 1.2 ounces 
(7.2 teaspoonfuls).  This is much less than a unit of blood (about 16 ounces) typically given during a 
blood donation. 
Some drugs may have dangerous interactions with lofexidine and should not be used together.  Using 
lofexidine and beta-receptor blockers (to treat high blood pressure) together may cause a very low 
heart rate.  Using lofexidine with alcohol, sedatives, and/or antihistamines may enhance central 
nervous system depressant effects (for example excessive sleepiness).  Before starting any new 
medications, you should talk with your study doctor. 
Nicotine Replacement Medications:  You should not smoke if you are being treated with nicotine 
replacement medications since this may result in high levels of nicotine in your blood.  Signs and 
symptoms of high levels of nicotine in your blood are nausea, vomiting, abdominal pain, diarrhea, 
weakness, dizziness, loss of color, cold sweats, tremor, mental confusion, headache, and disturbed 
hearing and vision. 
In addition to the risks or discomforts listed above, there may be other risks that are currently not 
known.  Also the risks or discomforts described may occur more often or be more severe than has 
been seen before. 
REPRODUCTIVE RISKS 
The effects of lofexidine on the human fetus are unknown.  High doses of lofexidine given to 
pregnant mice, rats, and rabbits caused a reduction in fetal weights and slight increase in fetal 
resorptions (loss of fetus with the fetus absorbed within the pregnant animal's body).  If you 
become pregnant while in this research study, an injury to the fetus may occur that has not been 
seen before.  Additionally, the effects on an infant, through breast feeding (nursing), are unknown. 
If you become pregnant during the study or within 30 days after study completion, notify your study 
doctor immediately.  Your pregnancy will be followed to outcome. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 9 of 13 
NEW FINDINGS 
Your study doctor will tell you of any information learned during the course of the study that might cause 
you to change your mind about taking part in this research study.  You may contact the study doctor at 
any time after your participation ends to find out if any new information about this study has become 
available. 
POSSIBLE BENEFITS 
Your opioid withdrawal symptoms may be reduced while participating in this study but we cannot 
guarantee that you will receive any benefits by taking part in this study.  Your participation in the study 
will contribute to information about this non-addictive study drug and may benefit other patients 
addicted to opioids in the future. 
PAYMENT TO SUBJECT FOR PARTICIPATION 
For your participation, you will be paid for your time and inconvenience as follows: 
Screening (up to 3 visits): 
 
Days 1-3 (In-clinic): 
 
 
 
Days 1-7 (In-clinic): 
 
 
 
 
 
Days 4-7 (Outpatient) 
 
Days 8-14 (Outpatient): 
 
 
  The maximum compensation you may receive for your 
participation in this research study is 
, in the event you require 3 screening visits, you receive 
in-clinic treatment on Days 1 through 7, and you participate through Day 14. 
If you require transportation for clinic visits, you may be reimbursed for expenses (after you submit 
receipts) or transportation may be provided by the study site. 
You will receive compensation by cash, check, or vouchers in accordance with your local study site’s 
policies. 
COSTS 
You do not have to pay for your stay in the unit, study visits, and for any treatment or testing done as 
part of this research study. 
ALTERNATIVE TREATMENTS 
No non-opioid drugs are currently approved by the U.S. FDA for the treatment of opioid withdrawal 
signs and symptoms.  You do not have to take part in this research study, however, to receive 
treatment for your condition.  If you decide not to take part in this study, a study doctor will discuss 
alternative treatments with you.  Two prescription drugs (buprenorphine and methadone) are available 
to treat your withdrawal symptoms.  Both of these drugs are opioids and have side effects and risks 
associated with their use.  Individual and/or group counseling may also help your condition.  The study 
researchers will, at your request, refer you to public or private substance abuse treatment programs in 
your geographic area, at your own cost or through your regular health care provider.  Refusal to 
participate in this study will not affect other medical care for which you may be eligible. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 10 of 13 
CONFIDENTIALITY AND RELEASE OF MEDICAL RECORDS 
We will protect information about you and your taking part in this research study to the best of our ability.  
To help protect your privacy, the study sponsor (US WorldMeds) has obtained a Certificate of 
Confidentiality from the National Institutes of Health (NIH).  With this certificate, the researchers cannot be 
forced to disclose information that may identify you, even by a court subpoena, in any federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. 
The Certificate of Confidentiality does not prevent the researchers, however, from disclosing voluntarily, 
without your consent, information that would identify you as a participant in the research study under 
certain circumstances (for example, abuse, neglect, harm to self, harm to others, and certain cases of 
communicable diseases).  In addition, absolute confidentiality cannot be guaranteed because medical 
records and study information that identify you may need to be audited or evaluated by authorized staff 
from the U.S. FDA, Institutional Review Board (IRB), the study sponsor (US WorldMeds), and other 
health authorities to meet their specific requirements.   
These agencies and researchers are bound by rules of confidentiality, however, and they make every 
effort not to release information that identifies you.  If information about this study is published, your 
name, initials, or any other identifying information will not be given. 
Data collected during the study (including laboratory specimens, medical records, and other data forms 
and records) will be stored in a way that does not identify you by name.  Research and clinical records 
will be stored in a locked cabinet.  Only selected study researchers will have access to this information 
and they are bound by rules of confidentiality not to reveal identifying information to others. 
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. 
RESEARCH RELATED INJURY 
If you are injured as a result of the study drug or study procedures performed during your inpatient 
participation in this research study, you will receive medical care at the study site or an emergency 
department as clinically necessary.   
If you are injured as a result of the study drug or study procedures performed during your outpatient 
participation in this research study, you should seek medical attention at the health care provider of 
your choice or an emergency department if necessary.  The sponsor or study site will cover the 
medical expenses necessary to treat the injury only to the extent that such costs are not covered by your 
health insurance policy, by a government program, or by any other third party. 
You must follow the directions of the study doctor to be eligible for this coverage. 
Neither the sponsor nor the study doctor/study site has a program in place to provide other 
compensation in the event of an injury. 
LEGAL RIGHTS 
You do not waive any legal rights by signing this Subject Information and Consent Form. 
VOLUNTARY PARTICIPATION 
Your decision to take part in this research study is completely voluntary.  There will not be any penalty 
or loss of benefits to you if you decide not to take part.  You will be informed of any significant new 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 11 of 13 
information that becomes available during the course of the study that might affect your decision to 
continue your participation in the study. 
You may drop out of this study at any time.  Because there may be risks associated with this decision, 
you should inform the study staff.  They will assist you in properly ending your participation, 
including returning to the clinic for tests if you are an outpatient.   
If you leave the study early, you will be assisted in finding other substance abuse treatment 
programs in your geographic area, if you so desire, at your own cost or through your regular 
health care provider. 
WITHDRAWAL 
Your doctor, the sponsor company, or the FDA has the right to stop your participation in the study at any 
time, with or without your consent, for any of the following reasons: if you have an adverse effect from 
the study drug; if you need a treatment not allowed in this study; if you fail to follow the study 
procedures; if you become pregnant; or if the study is canceled by the FDA or the sponsor 
company.  The sponsor may decide to stop the study and your access to the study under certain 
circumstances, even if the study drug appears to be safe and effective.  You may drop out of this 
research study at any time, without penalty (see above). 
CONTACT FOR QUESTIONS 
If you have any questions about your participation in this research study, or if you feel that you 
have experienced a research-related injury or reaction to the study drug, contact the study 
doctor at the telephone number listed on page 1 of this form. 
This study was reviewed by 
  An IRB reviews research to 
protect the rights and welfare of study participants.  If you have problems, concerns, suggestions, 
questions or information about the study, and for information regarding research subject's rights, 
please call 
 
(toll free). 
Although 
 has approved the information provided in this informed consent form and has 
granted approval for the investigator to conduct the study this does not mean
 has approved 
your participation in the study.  You must evaluate the information in this informed consent form for 
yourself and decide whether or not you wish to participate. 
AUTHORIZATION TO USE AND DISCLOSE PERSONAL HEALTH INFORMATION FOR 
RESEARCH 
The United States government has issued a new privacy rule to protect the privacy rights of patients.  
This rule was issued under a law called the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  The Privacy Rule is designed to protect the confidentiality of your personal health 
information.  The document you are reading, called an “Authorization,” describes your rights and 
explains how your health information will be used and disclosed (shared). 
In working with the sponsor, the study doctors will use and share personal health information about 
you.  This is information about your health that also includes your name, address, telephone number, 
or other facts that could identify the health information as yours.  This includes information in your 
medical record and information created or collected during the study.  This information may include 
results of your medical history, physical exam, and laboratory tests (blood, urine, and ECG).  Some of 
these tests may have been done as part of your regular care.  The study doctor will use this 
information about you to complete this research. 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 12 of 13 
In most cases, the study doctor will use your initials and assign a code number to your information 
that is shared with the sponsor.  The sponsor and its representatives may review or copy your 
personal health information at the study site.  Regulatory authorities and the IRB may also review or 
copy your information to make sure that the study is done properly or for other purposes required by 
law. 
By signing this Authorization, you allow the study doctor to use your personal health information to 
carry out and evaluate this study.  You also allow the study doctor to share your personal health 
information with: 
• 
the sponsor and its representatives; 
• 
 
• 
the U.S. FDA; and 
• 
other regulatory agencies. 
Your personal health information may be further shared by the groups above.  If shared by them, 
the information will no longer be covered by the Privacy Rule.  These groups, however, are committed 
to keeping your personal health confidential. 
You have the right to see and get a copy of your records related to the study for as long as the study 
doctor has this information.  By signing this Authorization, however, you agree that you might not be able 
to review or receive some of your records related to the study until after the study has been completed. 
You may choose to withdraw this Authorization at any time, but you must notify the study doctor in 
writing.  Give your written withdrawal notice to your study doctor if you are being treated as an 
inpatient.  If you are being treated as an outpatient, send your written withdrawal notice to the study 
doctor at the address listed on page 1 of this form. 
If you withdraw from the study and withdraw your Authorization, no new information will be collected for 
study purposes unless the information concerns an adverse event (a bad effect) related to the study.  If 
an adverse event occurs, your entire medical record may be reviewed.  All information that has already 
been collected for study purposes, and any new information about an adverse event related to the study, 
will be sent to the study sponsor. 
If you withdraw from the study but do not withdraw your Authorization, new personal health information may 
be collected until this study ends. 
This authorization does not have an expiration date.  If you do not withdraw this Authorization in writing, it 
will remain in effect indefinitely.  Your study doctor will keep this Authorization for at least 6 years. 
If you do not sign this Authorization, you cannot participate in this research study or receive study-related 
treatment.  If you withdraw this Authorization in the future, you will no longer be able to participate in this 
study.  Your decision to withdraw your Authorization or not to participate will not involve any penalty or 
loss of access to treatment or other benefits to which you are entitled. 
 
 


TEMPLATE DOCUMENT- NOT APPROVED FOR SINGLE SITE USE 
Protocol Number: USWM-LX1-3003-2 
 
Subject Initials: ________ 
 
Consent Date:  January 16, 2015 
 
Page 13 of 13 
 
VOLUNTEER'S STATEMENT: 
A Phase 3, Open-Label, Safety Study of Lofexidine 
 
 
I have been given a chance to ask questions about this research study.  These questions have been 
answered to my satisfaction.  I may contact the study doctor if I have any more questions about taking 
part in this study.  The study doctor or the company he/she is employed by is being paid by the 
sponsor for my participation in this study. 
I understand that my participation in this research project is voluntary.  I know that I may quit the study 
at any time without harming my future medical care or losing any benefits to which I might be 
entitled.  I also understand that the investigator in charge of this study may decide at any time that 
I should no longer participate in this study. 
If I have any questions about my rights as a research subject in this study I may contact 
 at 
(toll free). 
By signing this form, I have not waived any of my legal rights. 
I have read and understand the above information.  I agree to participate in this study.  I understand 
that I will be given a copy of this signed and dated form for my own records. 
 
 
__________________________________  
 
_______________ 
Study Participant (signature) 
  
 
 
Date 
 
__________________________________ 
Print Participant’s Name 
 
 
__________________________________  
 
_______________ 
Person who explained this study (signature)  
 
Date 
 
 

Prot_000.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
PROTOCOL NUMBER / AMENDMENT: USWM- LX1-3003-2 / 02 
 
  
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
 
 
TITLE: 
A Phase 3, Open-Label, Safety Study of Lofexidine 
 
 
DOCUMENT DATE: 21MAY2015 
NDA NUMBER: 209229 
NCT NUMBER: NCT02363998 


US WorldMeds, LLC 
Clinical Study Report – USWM-LX1-3003-2 
16.1 
STUDY INFORMATION 
16.1.1 
PROTOCOL AND AMENDMENTS 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 1


Confidential Information 
 
Page 1 of 120 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Open-Label, Safety Study of Lofexidine 
Protocol Number: 
USWM-LX1-3003-2 
Product: 
Lofexidine 
Investigational New Drug (IND) Number: 
IND 47,857 
Development Phase of Study: 
Phase 3 
Medical Monitor: 
 
Sponsor: 
US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 
Louisville, KY  40207 
Protocol Date: 
February 3, 2012 
Amendment No. 01 
January 22, 2015 
Amendment No. 02 
May 21, 2015 
Confidentiality Statement:  The information in this document contains trade secrets 
and commercial information that are privileged or confidential and that may not be 
disclosed without the written consent of US WorldMeds, LLC.  Acceptance of this 
document constitutes the agreement of the recipient that this information will not be 
disclosed to others, except to the extent necessary for Institutional Review Board 
procedures and to obtain written informed consent from those persons to whom test 
drug may be administered. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 2


209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 3


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 3 of 120 
2 PROTOCOL AMENDMENT SUMMARY 
This section provides a summary of major changes made in this current amendment (No. 02) 
to the protocol for Study USWM-LX1-3003-2 along with changes made in the prior 
amendment (No. 01).  Section 23 provides a detailed accounting of all changes made in these 
amendments. 
SUMMARY OF MAJOR CHANGES 
Amendment No. 02 (May 21, 2015) 
 The protocol was revised to update subject reimbursement to account for up to 
3 in-office screening visits (see Section 14.4). 
 The protocol was clarified to indicate that subjects receiving lofexidine treatment on 
an outpatient basis are required to take a dose of lofexidine in the clinic at each daily 
clinic visit, thus allowing assessments to be performed before and after dosing as 
detailed in Table 1. 
 The protocol was clarified to indicate that should confirmatory vital sign 
measurements be required with waiting between measurements, the timing of the 
measurement will not be considered a protocol deviation (i.e., outside the protocol-
specified window). 
 The protocol was revised to add an electrocardiogram at 3.5 hours after dosing (or as 
close to this time as possible) for the end-of-study visit (see Section 15.5.3). 
 The protocol was revised to clarify syphilis testing results and interpretation for 
determination of subject study eligibility (see Table 4 in Section 15.5.4.2). 
 Three urinary drug screen panels were added, including oxycodone, phencyclidine 
and methylenedioxymethamphetamine (see Section 15.5.4.3).  
 
Amendment No. 01 (January 22, 2015) 
 The protocol was revised to allow enrollment of subjects with clinical treatment goals 
for full or partial withdrawal from any opioid (including methadone and 
buprenorphine), which would be expected to elicit opioid abstinence syndrome 
requiring treatment for at least 7 days.  Treatment goals may include abrupt and total 
withdrawal, agonist-assisted total withdrawal, dose reduction of maintenance 
treatment (e.g., methadone, buprenorphine), and transition from an opioid or opioid 
agonist to naltrexone or buprenorphine maintenance.  An attempt will be made to 
include a minimum of 50 subjects each treated for clinical scenarios involving 
methadone or buprenorphine treatment (i.e., a total of 50 subjects receiving full or 
partial dose reduction from methadone, methadone-assisted withdrawal, and other 
methadone treatment scenarios and a total of 50 subjects receiving full or partial dose 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 4


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 4 of 120 
reduction from buprenorphine, transition to buprenorphine maintenance, and other 
buprenorphine treatment scenarios).  The change was introduced to enable the study 
of lofexidine’s utility in any situation in which mitigation of opioid withdrawal 
symptoms would be beneficial to reaching the end treatment goal.  Both 
buprenorphine and methadone clinical scenarios are being evaluated as clinically 
relevant scenarios where lofexidine’s use is likely.  Results of prior interaction studies 
do not suggest a significant safety concern with coadministration of lofexidine and 
both methadone and buprenorphine.  Further evaluation of the safety and clinical 
utility of lofexidine coadministered with methadone or buprenorphine will help 
confirm that a contraindication for use of lofexidine with agonists is unnecessary. 

The protocol was revised to use the Mini International Neuropsychiatric Interview
(M.I.N.I.) rather than the Structured Clinical Interview for DSM-IV-TR Axis I
Disorders (SCID) to establish the appropriate dependence diagnosis on opioids,
exclude other drug dependency, and determine the absence of major psychiatric
disorders.  M.I.N.I. is being used for consistency with eligibility assessment in
companion study, USWM-LX1-3003-1.  Like SCID, the M.I.N.I. is a validated scale
(Sheehan et al., 1998) and is commonly used in clinical practice and research studies.

Number of subjects needed for enrollment was increased from 200 to 400 to
250 to 500 based on the projected number of subjects completing 7 days of lofexidine
treatment in the companion study (USWM-LX1-3003-1) and FDA’s safety database
requirements.  Enrollment in USWM-LX1-3003-2 will continue until a minimum of
300 subjects across the lofexidine studies have received active treatment at clinically
relevant doses for at least 7 days.

Number of study sites was increased from 10 to approximately 20 to account for the
potentially higher enrollment requirements and target study completion timelines.

The protocol was revised from flexible dosing to standardized dosing of 7 days of
lofexidine treatment, starting at 3.2 mg daily (0.8 mg QID), with lowering of the dose
allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the subject’s
individual treatment goal and response per clinical judgment of the Principal
Investigator.  The standard dosing approach is being adopted to limit variability across
sites and treatment scenarios to ensure interpretability of safety data at clinically
relevant doses and to evaluate the same doses as used in the controlled programs with
demonstrated efficacy.

The protocol was revised to require 3 days of mandatory in-clinic (inpatient housing/
clinic facilities) treatment with lofexidine (Days 1-3) and then, per clinical judgment
of the Principal Investigator, subjects can continue to receive all 4 daily doses of
lofexidine in the clinic or can be treated as outpatients for the remaining
4 days of mandatory lofexidine treatment (Days 4-7).  Subjects can continue receiving
lofexidine on a semi-standardized taper in an outpatient setting as long as acute
withdrawal symptoms persist at the Principal Investigator’s discretion; however, in no
event is treatment to exceed an additional 7 days (maximum of
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 5


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 5 of 120 
14 days treatment over entire study).  The required initial 3 days of in-clinic treatment 
was introduced to enable more frequent safety monitoring during anticipated peak 
withdrawal and initiation of lofexidine therapy.  Outpatient treatment for continuation 
of therapy begins at Day 4 to enable assessment, as clinically appropriate at the 
discretion of the Principal Investigator, in a more flexible, real-world setting as 
patients with a variety of treatment goals, as being studied in the current design, may 
not require a longer-term clinic stay and in many situations it may be impractical to 
require inpatient treatment for more than a few days (e.g., work schedules). 

The protocol was revised to require daily (rather than every other day) assessments,
including during in-clinic treatment and at daily clinic visits during outpatient
treatment.  As the primary objective of the study is to assess safety of lofexidine at
clinically relevant doses, daily evaluations regardless of inpatient or outpatient status
are appropriate.

The Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) was added because
this scale has been evaluated in nearly all other lofexidine studies in opioid
withdrawal, serving as the instrument to evaluate efficacy as the primary endpoint in
the 2 pivotal programs conducted for the drug; and the SOWS-Gossop data will be
used to evaluate lofexidine’s effectiveness in a variety of open-label clinical scenarios
studied under the current protocol.

Requirements for vital signs were expanded during in-clinic treatment with lofexidine,
similar to requirements in the companion study (USWM-LX1-3003-1). Also a subject
diary (Appendix 3) was added if the required post-dose blood pressure/pulse
measurement cannot be obtained in the clinic.  These changes were introduced to
ensure the most robust safety data collection possible during the
in-clinic portion of the study and providing a mechanism for additional data collection
in the outpatient setting, consistent with the primary objective of the study.

A fingerprick blood sample concurrently with each scheduled ECG was added to
enable QTc-concentration analyses.

A fingerprick blood sample was added for analysis of plasma lofexidine concentration
to monitor compliance during outpatient treatment.

Columbia Suicide Severity Rating Scale (C-SSRS) was added as a safety assessment,
consistent with the current guidance to assess suicidality in all clinical studies
involving central nervous system acting drugs.
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 6


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 6 of 120 
3 SYNOPSIS 
Title 
A Phase 3, Open-Label, Safety Study of Lofexidine 
Objective 
The primary objective of the study is to continue to investigate the safety of 
lofexidine when administered for at least 7 days at clinically relevant doses 
(3.2 or 2.4 mg/day) to alleviate symptoms of acute withdrawal from opioids 
in a variety of clinical scenarios in both in-clinic and outpatient settings.  
The effectiveness of lofexidine is also of interest. 
Study Design Multicenter, open-label study in the United States in which subjects will 
receive lofexidine treatment for 7 days, starting at a dose of 3.2 mg daily 
(0.8 mg QID), with lowering of the dose allowed to 2.4 mg daily (0.6 mg 
QID) if required for tolerability based on the subject’s individual treatment 
goal and response per clinical judgment of the Principal Investigator.  Note 
that all subjects will start lofexidine administration (Day 1) on the first day 
of his/her planned opioid agonist dose reduction/discontinuation regardless 
of the clinical situation in which the subject is seeking treatment (see 
Inclusion Criterion No. 3).  All subjects will receive all 4 doses of 
lofexidine in a clinic setting for the first 3 days (Days 1-3) and then, per 
clinical judgment of the Principal Investigator, subjects can continue to 
receive lofexidine doses in a clinic setting or can be treated outside of the 
clinic (outpatient) for the remaining 4 days of mandatory lofexidine 
treatment (Days 4-7).  Per Principal Investigator judgment, subjects can 
continue lofexidine treatment beyond Day 7 on an outpatient basis only for 
up to an additional 7 days (Days 8-14).  Note that lofexidine dosing may be 
stopped at any time during Days 8-14.  No subject will receive lofexidine 
for more than 14 days total.  Subjects will receive a telephone follow-up call 
30 days after their last dose.  
During in-clinic treatment, subjects must take lofexidine within a 1-hour 
window, 30 minutes before or after 8 AM and within a 30-minute window, 
15 minutes before or after 1 PM, 6 PM, and 11 PM.  In the event a subject is 
not dosed within this window as a result of completion of confirmatory vital 
sign assessments (Section 10.4), this will not constitute as a protocol 
deviation.  Source documents must note, however, the reason for dose 
delay.  For subjects receiving outpatient treatment (elective) on Days 4-7 
and those continuing lofexidine treatment in a mandatory outpatient setting 
for up to an additional 7 days (Days 8-14), prescribed dosing will remain on 
the same QID schedule (8 AM, 1 PM, 6 PM, 11 PM).   
Sites 
Approximately 20 (Target:  ≥3-4 subjects/site/month.  Recruitment time: 
4 to 10 months, depending on total enrollment requirements) 
Inclusion 
Criteria 
1. Be able to verbalize understanding of the consent form, able to provide 
written informed consent, and verbalize willingness to complete study 
procedure . 
2. Be male or female at least 18 years of age. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 7


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 7 of 120 
Inclusion 
Criteria 
(continued) 
3. Have current dependence, according to the Mini International 
Neuropsychiatric Interview (M.I.N.I.), on any opioid (including 
methadone and buprenorphine maintenance treatment). 
4. Be seeking treatment for partial or total withdrawal from current opioid 
and expected, as determined by the Principal Investigator, to benefit 
from lofexidine treatment for at least 7 days at clinically relevant doses 
(3.2 or 2.4 mg/day).  This can include a variety of clinical situations 
where opioid withdrawal illness is likely to occur.  Examples include:  
 abrupt and total withdrawal (including from methadone and 
buprenorphine); 
 agonist-assisted total withdrawal; 
 dose reduction of maintenance treatment (e.g., of methadone or 
buprenorphine); and 
 transition from an opioid agonist to naltrexone or buprenorphine 
maintenance. 
5. Urine toxicology screen positive for opioid(s) relevant to the subject’s 
withdrawal treatment goal (can include methadone and buprenorphine) 
at Screening. 
 
6. If female and of childbearing potential, subject must agree to use one of 
the following methods of birth control: 
 oral contraceptives; 
 patch; 
 barrier (diaphragm, sponge or condom) plus spermicidal 
preparations; 
 intrauterine contraceptive system; 
 levonorgestrel implant; 
 medroxyprogesterone acetate contraceptive injection; 
 complete abstinence from sexual intercourse; 
 hormonal vaginal contraceptive ring; or 
surgical sterilization or partner sterile (must have documented proof). 
Exclusion 
Criteria 
1. Be a female subject who is pregnant or lactating. 
2. Have a very serious medical illness not under control as detailed below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 8


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 8 of 120 
Exclusion 
Criteria 
(continued) 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (subject is excluded if 
positive for active syphilis as per required laboratory tests; see 
also Section 15.5.4.2) and hepatitis (positive results do not 
exclude a prospective subject from participation unless there is 
an indication of active liver disease); and 
 tuberculin test (purified protein derivative [PPD]) and/or a chest 
x-ray (a positive PPD result does not exclude a prospective 
subject from participation, but if diagnostic tests [e.g., chest 
x-ray] indicate that active disease is present, the subject will be 
excluded from participation; see also Section 15.5.4.2). 
 
 Have active self-reported acquired immune deficiency syndrome 
(AIDS) or self-reported human immunodeficiency virus (HIV) 
positive status and taking retroviral medications currently or within 
the past 4 weeks. 
 Have an unstable psychiatric condition (e.g., suicide risk, per 
Investigator judgment). 
3. Current dependence (based on the M.I.N.I.) on any psychoactive 
substance (excluding caffeine, nicotine, and the subject’s current opioid-
dependence agent, which can include methadone or buprenorphine for 
example, in agonist-maintained subjects) that requires detoxification or 
dose reduction as part of the pre-defined individual subject withdrawal 
treatment goal. 
4. Have participated in an investigational drug study within the past 
30 days. 
5. Have history of lofexidine exposure in a prior clinical trial or otherwise. 
 
6. Abnormal cardiovascular exam at Screening, including any of the 
following: 
 clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled arrhythmia, or 
QTcF intervals greater than 450 msec for males and greater than 
470 msec for females); 
 resting pulse less than 55 bpm or symptomatic bradycardia; 
 resting systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
 resting diastolic blood pressure less than 65 mmHg; 
 resting blood pressure greater than 155/95 mmHg; or 
 prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the above 
criteria, the value should be confirmed by repeating the measurement 
(twice, if necessary).  If 2 of 3 values meet the above criteria, the subject 
will be excluded from participation. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 9


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 9 of 120 
Exclusion 
Criteria 
(continued) 
7. To avoid drug-drug interactions, subjects requiring the following will be 
excluded: 
 
tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and 
 
beta-receptor blockers, to avoid the risk of excessive bradycardia. 
N 
Total enrollment will depend on subject drop-out rates.  Approximately 
250 to 500 subjects:  enrollment will continue until a minimum total of 300 
subjects (across this protocol and earlier lofexidine clinical studies expected 
to meet FDA safety database requirements) have been treated with clinically 
relevant doses of lofexidine for a minimum of 7 days.  A target of at least 
50 subjects each treated for clinical scenarios involving methadone or 
buprenorphine treatment will be enrolled (i.e., a total of 50 subjects 
receiving full or partial dose reduction from methadone, methadone-assisted 
withdrawal, and other methadone treatment scenarios and a total of 50 
subjects receiving full or partial dose reduction from buprenorphine, 
transition to buprenorphine maintenance, and other buprenorphine treatment 
scenarios). 
Safety 
Endpoints 
 Occurrence, seriousness, severity, and causality assessment of adverse 
events (AEs). 
 Occurrence of AEs of special interest (i.e., orthostatic hypotension, 
orthostatic bradycardia, syncope). 
 Occurrence of AEs not related to opioid withdrawal. 
 Descriptive evaluation of vital signs (actual and change from baseline) 
for each time point. 
 Descriptive evaluation of the three C-SSRS subscales (suicidal ideation, 
suicidal behavior, and intensity of suicidal ideation). 
 Shifts from baseline in physical examination findings. 
 Descriptive evaluation of clinical laboratory tests of hematology, 
chemistry, and urinalysis (actual and change from baseline).   
 Descriptive evaluation of ECG (actual and change from baseline). 
Effectiveness 
Endpoints 
 Number/proportion of subjects successfully completing their pre-defined 
withdrawal treatment goal (e.g., planned detoxification/ transition) as 
assessed by the Principal Investigator. 
 Distribution of number of days required to complete withdrawal 
treatment goal by category. 
 Descriptive evaluation of SOWS-Gossop. 
 Descriptive evaluation of COWS numerical score and severity score 
(i.e., mild, moderate, moderately severe, severe). 
 Concomitant medication analysis. 
 Evaluation of subject treatment status 30 days after last dose. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 10


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 10 of 120 
Duration 
23 days (maximum duration per subject, including screening) 
Visits 
All subjects will undergo screening up to 9 days before study admission. 
Days 1-3 
 In-clinic setting: Subjects may be admitted to the clinic on Day -1. 
Days 4-7 
 In-clinic setting OR daily visits for 4 days if outpatient 
Days 8-14 
 Daily outpatient visits for up 7 days 
Day 30 
 Telephone follow-up contact 
Safety 
Assessments 
The following safety assessments will be performed daily unless otherwise 
specified below: 
 Occurrence, seriousness, severity, and causality assessment of AEs; 
 Vital signs during in-clinic treatment (Days 1-3 mandatory; Days 4-7 if 
subject receives all lofexidine doses in the clinic), including blood 
pressure and pulse at rest (sitting [or recumbent if necessary because of 
an adverse event]) and standing (if able) before every dose and 3.5 hours 
after administration of study medication at 8 AM, 1 PM, and 6 PM 
(respiration and temperature before 8 AM dose only); 
 Vital signs during outpatient treatment (Days 4-7 optional; Days 8-14 if 
subject continues taking lofexidine), including blood pressure and pulse 
at rest (sitting [or recumbent if necessary because of an adverse event]) 
and standing (if able) before an in-clinic dose of lofexidine and 3.5 hours 
after dosing on Days 4-13 and once before any dose on Day 14 or, if 
applicable, at discontinuation from the study (note: if subjects cannot 
stay in the clinic for measurement of the 3.5-hour post-dose vital signs, 
they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point, with values 
recorded in a subject diary); 
 12-lead ECGs (in duplicate) recorded as follows: 
 Day 1 before the first dose at 8 AM and at 3.5 hours after dosing; 
 Before subject’s last dose and 3.5 hours after dosing (or as close to 
this time as possible) or, if applicable, at discontinuation from the 
study; 
 Clinical laboratory tests as clinically warranted and at discontinuation 
from the study;  
 Complete physical examination 3 to 4 hours after first dose on Day 1, as 
clinically warranted, and at discontinuation from the study; 
 Pregnancy test at discontinuation from the study; 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 11


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 11 of 120 
Safety 
Assessments 
(continued) 
 C-SSRS 3.5 hours after the first dose (8 AM) during in-clinic treatment, 
once daily before an in-clinic dose of lofexidine during outpatient 
treatment, or, if applicable, at discontinuation from the study; 
 A qualitative urine drug screening (by on-site use of “dipsticks”) for 
specific drug or metabolite classification will be done every day during 
in-clinic treatment to monitor for contraband and every day during 
outpatient treatment to monitor for illicit drug use; 
 A fingerprick blood sample for pharmacokinetic (PK) analysis will be 
collected concurrently with each scheduled ECG; and 
 A fingerprick blood sample will be collected during outpatient treatment 
when the subject reports to the clinic each day (before next scheduled 
dose) for analysis of plasma lofexidine concentration to monitor 
compliance. 
A follow-up telephone contact will be attempted 30 days after the subject’s 
last dose of study drug for an adverse event evaluation and an evaluation of 
the subject’s current treatment status (e.g., relapse, current psychosocial 
treatment, successful entry into a methadone, buprenorphine, or naltrexone 
program). 
Effectiveness 
Assessments 
The following effectiveness assessments will be performed daily unless 
otherwise specified below: 
 SOWS-Gossop 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before an in-clinic dose of lofexidine during 
outpatient treatment; 
 COWS 3.5 hours after the first daily dose during in-clinic treatment; 
once daily before an in-clinic dose of lofexidine during outpatient 
treatment; 
 Completion of withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator;  
 Concomitant medication use; and 
 Evaluation of subject treatment status 30 days after last dose. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 12


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 12 of 120 
4 TABLE OF CONTENTS 
1
SIGNATURE PAGE .......................................................................................................2
2
PROTOCOL AMENDMENT SUMMARY ...................................................................3
3
SYNOPSIS ......................................................................................................................6
4
TABLE OF CONTENTS ..............................................................................................12
5
ABBREVIATIONS AND DEFINITION OF TERMS .................................................16
6
BACKGROUND AND SIGNIFICANCE ....................................................................18
6.1
Opioid Dependence ..................................................................................................18
6.2
Lofexidine Hydrochloride ........................................................................................18
6.3
Efficacy of Lofexidine .............................................................................................19
6.4
Safety of Lofexidine .................................................................................................20
6.5
Rationale for Dose Selection and Regimen ..............................................................21
6.6
Rationale for Outcome Measures .............................................................................21
7
STUDY OBJECTIVES .................................................................................................22
8
STUDY SPONSOR ......................................................................................................22
9
STUDY SITES AND INVESTIGATORS....................................................................22
10 
INVESTIGATIONAL PLAN .......................................................................................22
10.1 
Overall Design ..........................................................................................................22
10.2 
Number of Subjects ..................................................................................................23
10.3 
Duration of Study .....................................................................................................23
10.4 
Dose Hold and Discontinuation Criteria (2 of 3 Rule) .............................................23
11 
SELECTION OF STUDY POPULATION ..................................................................24
11.1 
Population Base ........................................................................................................24
11.2 
Study Entrance Requirements ..................................................................................24
11.2.1 
Inclusion Criteria .................................................................................................24
11.2.2 
Exclusion Criteria ................................................................................................25
11.3 
Screening Failures ....................................................................................................27
12 
INVESTIGATIONAL AGENTS ..................................................................................27
12.1 
Lofexidine Hydrochloride ........................................................................................27
12.2 
Dispensing Investigational Agent ............................................................................27
12.3 
Blinding Plan ............................................................................................................28
12.4 
Labeling ....................................................................................................................28
12.5 
Storage ......................................................................................................................28
12.6 
Record of Administration .........................................................................................28
12.7 
Used/Unused Supplies ..............................................................................................29
12.8 
Contraindications .....................................................................................................29
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 13


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 13 of 120 
13 
TREATMENT PLAN ...................................................................................................29
13.1 
Investigational Agent ...............................................................................................29
13.2 
Dose Administration ................................................................................................29
13.2.1 
Administration of Doses ......................................................................................29
13.2.2 
Dose Hold Criteria ...............................................................................................31
13.2.3 
Discontinuation Criteria ......................................................................................31
13.3 
Treatment Compliance .............................................................................................32
13.4 
Nicotine Replacement Therapy ................................................................................33
14 
STUDY PROCEDURES ..............................................................................................33
14.1 
Subject Recruitment and Consent ............................................................................33
14.2 
Screening ..................................................................................................................34
14.3 
Treatment Phase .......................................................................................................34
14.3.1 
Days 1-3 (Mandatory In-clinic) ...........................................................................34
14.3.2 
Days 4-7 (In-clinic/Outpatient) ...........................................................................34
14.3.3 
Days 8-14 (Outpatient Only) ...............................................................................35
14.4 
Subject Reimbursement ............................................................................................35
14.5 
Study Discontinuation ..............................................................................................35
14.5.1 
Subject Discontinuation .......................................................................................35
14.5.2 
Cardiovascular Events Requiring Subject Discontinuation From Study ............36
14.5.3 
Trial Discontinuation ...........................................................................................37
14.6 
Concomitant Therapy ...............................................................................................37
15 
CLINICAL EVALUATIONS .......................................................................................38
15.1 
Screening Assessments ............................................................................................41
15.2 
Baseline Assessments ...............................................................................................42
15.3 
Assessments During Treatment ................................................................................42
15.3.1 
Days 1-3 (Mandatory In-clinic) ...........................................................................42
15.3.2 
Days 4-7 (In-clinic/Outpatient) ...........................................................................43
15.3.3 
Days 8-14 (Outpatient Only) ...............................................................................44
15.3.4 
Study Discontinuation/End of Study ...................................................................45
15.3.5 
30-Day Telephone Follow-up Contact ................................................................46
15.4 
Effectiveness Assessment Methods .........................................................................46
15.4.1 
Assessment of Completion of Pre-Defined Withdrawal Treatment Goal ...........46
15.4.2 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) ..............................46
15.4.3 
Clinical Opiate Withdrawal Scale (COWS) ........................................................47
15.5 
Safety Assessment Methods .....................................................................................47
15.5.1 
Adverse Events ....................................................................................................47
15.5.1.1 
Withdrawal-Related Adverse Events ..............................................................48
15.5.2 
Vital Signs ...........................................................................................................48
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 14


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 14 of 120 
15.5.3 
12-Lead Electrocardiograms ...............................................................................49
15.5.4 
Clinical Laboratory Evaluations ..........................................................................50
15.5.4.1 
Standard Laboratory Tests ..............................................................................50
15.5.4.2 
Infectious Disease Panel and Syphilis Tests ...................................................51
15.5.4.3 
Urine Toxicology Screening ...........................................................................52
15.5.4.4 
Pregnancy Test ................................................................................................52
15.5.4.5 
Pharmacokinetic Sampling .............................................................................52
15.5.5 
Physical Examination ..........................................................................................53
15.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................53
15.6 
Other Assessments ...................................................................................................53
15.6.1 
Prior Medications ................................................................................................53
15.6.2 
Concomitant Medication Administration ............................................................53
16 
REGULATORY AND REPORTING REQUIREMENTS ...........................................53
16.1 
Good Clinical Practices ............................................................................................53
16.2 
FDA Forms 1572 and Financial Disclosure .............................................................54
16.3 
Institutional Review Board Approval ......................................................................54
16.4 
Informed Consent/HIPAA Authorization ................................................................54
16.5 
Drug Accountability .................................................................................................55
16.6 
Outside Monitoring ..................................................................................................55
16.6.1 
Medical Monitor ..................................................................................................55
16.6.2 
Clinical Monitors .................................................................................................55
16.7 
Adverse Event Reporting .........................................................................................56
16.8 
Serious Adverse Events (SAEs) ...............................................................................57
16.9 
Pregnancy .................................................................................................................58
17 
STATISTICAL APPROACH .......................................................................................58
17.1 
General Considerations ............................................................................................58
17.2 
Assessment of Effectiveness ....................................................................................58
17.3 
Assessment of Safety ...............................................................................................59
18 
DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) ............................60
18.1 
Data Collection .........................................................................................................60
18.2 
Electronic Data Capture ...........................................................................................60
18.3 
Data Analysis ...........................................................................................................60
18.4 
Study Documentation and Records Retention .........................................................60
18.5 
Confidentiality ..........................................................................................................61
18.5.1 
Confidentiality of Data ........................................................................................61
18.5.2 
Confidentiality of Subject Records .....................................................................61
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 15


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 15 of 120 
19
DISSEMINATION AND PUBLICATION OF STUDY RESULTS ...........................62
20
PROTOCOL ADHERENCE AND AMENDMENTS..................................................62
21
QUALITY CONTROL AND QUALITY ASSURANCE ............................................62
22
REFERENCES ..............................................................................................................63
23
PROTOCOL AMENDMENT DETAILS .....................................................................64
TABLES 
Table 1. Schedule of Study Assessments ...............................................................................39
Table 2. SOWS-Gossop Scoring Method ...............................................................................47
Table 3. Hematology, Chemistry, and Urinalysis Tests .........................................................51
Table 4. Syphilis Testing Sequence .......................................................................................52
Table 5. Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)     
USWM-LX1-3003-2, Amendment No. 01 (January 22, 2015) ...............................65
Table 6. Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 
(January 22, 2015)    USWM-LX1-3003-2, Amendment No. 02 
(May 21, 2015) .........................................................................................................97
APPENDICES 
Appendix 1 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
Appendix 2 
Clinical Opiate Withdrawal Scale (COWS) 
Appendix 3 
Subject Diary 
Appendix 4 
Short-term Withdrawal Treatment Goal 
Appendix 5 
Columbia Suicide Severity Rating Scale (C-SSRS) Baseline Version 
Appendix 6 
Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version 
Appendix 7 
Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events 
Appendix 8 
Procedure for Applying for a Certificate of Confidentiality 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 16


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 16 of 120 
5 ABBREVIATIONS AND DEFINITION OF TERMS 
Abs 
Absolute 
AE(s) 
Adverse Event(s) 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT/SGPT 
Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
Anti-HCV 
Hepatitis C Virus Antibody 
aPTT 
Activated Partial Thromboplastin Time 
AST/SGOT 
Aspartate Aminotransferase/Serum Glutamic-Oxaloacetic 
Transaminase 
BP 
Blood Pressure 
bpm 
beats per minute 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CIA 
Chemiluminescence Immnoaasay 
CLIA 
Clinical Laboratory Improvement Act of 1988 
CO2 
Carbon Dioxide 
COWS 
Clinical Opiate Withdrawal Scale 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DAWN 
Drug Abuse Warning Network 
DBP/dBP 
Diastolic Blood Pressure 
DHHS 
Department of Health and Human Services 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - Fourth 
Edition 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EIA 
Enzyme Immunoassay 
eCRF(s) 
Electronic Case Report Form(s) 
ED 
Emergency Department 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B Core Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 17


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 17 of 120 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MFI 
Multiplex Fluorescent Immunoassay 
MHOWS 
Modified Himmelsbach Opiate Withdrawal Scale 
M.I.N.I.
Mini International Neuropsychiatric Interview 
mmHg
Millimeters of Mercury 
msec
Millisecond 
NSAIDs
Nonsteroidal anti-inflammatory drugs 
NDA
New Drug Application 
NIMH
National Institute of Mental Health 
OL
Open Label 
PK
Pharmacokinetic 
PP
Per Protocol 
PPD
Purified Protein Derivative (skin test for tuberculosis) 
PT
Prothrombin Time 
QID
Four Times Daily 
QT
QT interval of an electrocardiogram 
QTc
Corrected QT interval 
QTcB
Corrected QT interval – Bazett’s method 
QTcF
Corrected QT interval – Fridericia’s method 
QTcI
Subject-specific QT 
RBC
Red Blood Cell 
RBM
Risk Based Monitoring 
RDW
Red Blood Cell Distribution Width 
RPR
Rapid Plasma Reagin 
SAE(s)
Serious Adverse Event(s) 
SAP
Statistical Analysis Plan 
SBP/sBP
Systolic Blood Pressure 
SOWS-Gossop
Short Opiate Withdrawal Scale of Gossop 
TEAEs
Treatment-Emergent Adverse Events 
T4
Free Thyroxine 
Tmax
Time of Maximum Plasma Drug Concentration 
TPPA
Treponema Pallidum Particle Agglutination Assay 
TSH
Thyroid-Stimulating Hormone 
UDS
Urine Drug Screening 
UK
United Kingdom 
ULN
Upper Limit of Normal 
US
United States 
USWM
US WorldMeds, LLC 
WBC
White Blood Cell 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 18


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 18 of 120 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 19


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 19 of 120 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 20


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
 
Page 20 of 120 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 21


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
 
Page 21 of 120 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 22


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 22 of 120 
7 STUDY OBJECTIVES 
The primary objective is to continue to investigate the safety of lofexidine when administered 
for at least 7 days at clinically relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms of 
acute withdrawal from opioids in a variety of clinical scenarios in both in-clinic and 
outpatient settings.  The effectiveness of lofexidine is also of interest.   
8 STUDY SPONSOR 
This study will be conducted under an Investigational New Drug (IND) application (#47,857) 
held by US WorldMeds, LLC. 
9 STUDY SITES AND INVESTIGATORS 
This study will be conducted at approximately 20 study sites in the US.  It is the 
responsibility of the Principal Investigators to make sure this protocol is conducted in full 
conformance with the ethical principles detailed in Section 16 of this protocol.  All data will 
be collected at the study sites on source documents and entered at the site into electronic case 
report forms (eCRFs) as described in Section 18.1 of this protocol. 
10 INVESTIGATIONAL PLAN 
10.1 Overall Design 
This is a Phase 3, multicenter, open-label study to evaluate the safety and effectiveness of 
lofexidine in alleviation of withdrawal signs and symptoms in subjects undergoing 
abstinence from any opioid, including methadone and buprenorphine maintenance treatment, 
which would likely require at least 7 days of lofexidine treatment for alleviation of 
withdrawal.  Any subject seeking treatment for partial or total opioid withdrawal will be 
eligible.  This can include a variety of clinical situations where opioid withdrawal illness is 
likely to occur, such as (but not limited to) abrupt and total withdrawal (including from 
methadone and buprenorphine), agonist-assisted total withdrawal, dose reduction of 
maintenance treatment (e.g., methadone, buprenorphine), and transition from an opioid 
agonist to naltrexone or buprenorphine maintenance.  Subjects will be evaluated for their 
compliance with protocol inclusion/exclusion criteria during a screening period, lasting up to 
9 days.  Approximately 250 to 500 subjects will receive lofexidine treatment for 7 days, 
starting at a dose of 3.2 mg daily (0.8 mg QID), with lowering of the dose allowed to 2.4 mg 
daily (0.6 mg QID) if required for tolerability based on the subject’s individual treatment 
goal and response per clinical judgment of the Principal Investigator.  Lofexidine 
administration should be initiated in concurrence with the change in opioid dose which is 
anticipated to elicit withdrawal symptoms (e.g., first day of dose reduction, or first day of 
abrupt cessation) or on the first day of emergence/anticipated emergence of such symptoms 
as determined at the Investigator’s discretion.  Details regarding the timing of lofexidine 
therapy initiation relative to change in opioid dose and onset/expected onset of symptoms 
should be captured in the source.  All subjects will receive all 4 doses of lofexidine in a clinic 
setting for the first 3 days (Days 1-3) and then, per clinical judgment of the Principal 
Investigator, subjects can continue to receive lofexidine doses in a clinic setting or can be 
treated outside of the clinic (outpatient) for the remaining 4 days of mandatory lofexidine 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 23


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 23 of 120 
treatment (Days 4-7).  Per Principal Investigator judgment, subjects can continue lofexidine 
treatment beyond Day 7 on an outpatient basis only for up to an additional 7 days 
(Days 8-14).  Note that lofexidine dosing may be stopped at any time during Days 8-14.  No 
subject will receive lofexidine for more than 14 days total.  All subjects receiving lofexidine 
treatment on an outpatient basis will be required to take a dose of lofexidine in the clinic at 
each daily clinic visit, with required clinical assessments performed before and after dosing 
as listed in Table 1 of Section 15.  Also during outpatient treatment, subjects will be required 
to undergo qualitative urine drug screening at each clinic visit. 
10.2 Number of Subjects 
The total enrollment in this study will depend on subject drop-out rates in this protocol.  
Enrollment will continue until a minimum total of 300 subjects (across this protocol and 
earlier lofexidine clinical studies expected to meet FDA safety database requirements) have 
been treated with clinically relevant doses of lofexidine for a minimum of 7 days.  It is 
estimated that approximately 250 to 500 subjects will be enrolled in this open-label study in 
order to accrue a sufficiently large safety database for evaluation.   
10.3 Duration of Study 
This study will be initiated after completion of the companion study, USWM-LX1-3003-1.  
The maximum duration of participation for each subject in USWM-LX1-3003-2 will be 
23 days, including the Screening period, which can last up to 9 days, followed by up to 
14 days of treatment with lofexidine. 
The study will be terminated when the database is judged to be sufficient, i.e., a minimum of 
300 subjects (across this protocol and earlier lofexidine clinical studies expected to meet 
FDA safety database requirements) have been treated with clinically relevant doses of 
lofexidine for a minimum of 7 days.  Enrollment is anticipated to take 4 to 10 months to 
achieve, with the total clinical duration of USWM-LX1-3003-2 anticipated to be 8 to 
12 months. 
10.4 Dose Hold and Discontinuation Criteria (2 of 3 Rule) 
When a blood pressure, heart rate, or QTcF interval value meets criteria for withholding a 
dose (Section 13.2.2) or discontinuation from the study (Section 13.2.3), the value needs to 
be confirmed by the site personnel by repeating the vital sign measurement or ECG 
recording, approximately 10 to 15 minutes later.  If the value is confirmed by the second 
measurement, the appropriate action will be taken (dose hold or study discontinuation) and 
the confirmatory value will be recorded in the subject’s source document and appropriate 
eCRF.  If the second value does not meet the specified criteria, a third measurement will be 
taken approximately 10 to 15 minutes later.  If this value is confirmatory, the appropriate 
action will be taken (dose hold or study discontinuation) and the last confirmatory value will 
be recorded in the subject’s source document and appropriate eCRF.  If the third value does 
not confirm the initial finding, then no action should be taken and the third value should be 
entered in the subject’s source and appropriate eCRF.  Note that should a second or third 
measurement be required with waiting between measurements, the timing of the 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 24


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 24 of 120 
measurement will not be considered a protocol deviation (i.e., outside the protocol-specified 
window). 
Whenever blood pressure, heart rate, or QTcF interval values meet dose hold or study 
discontinuation criteria, these are to be recorded on the subject’s eCRF as an adverse event 
(AE) or serious adverse event (SAE), as applicable.  Examples are: 
Item 
Record Adverse Event of: 
Resting Vital Signs 
 
SBP <90 mmHg and >20% below screen value 
Hypotension 
DBP <50 mmHg and >20% below screen value 
Hypotension 
Pulse <50 bpm and >20% below screen value 
Bradycardia 
Orthostatic Vital Signs 
 
SBP >25% below recumbent values 
Postural hypotension 
DBP <25% below recumbent values 
Postural hypotension 
Pulse >25% below recumbent values 
Postural bradycardia 
DBP = diastolic blood pressure, SBP = systolic blood pressure 
 
11 SELECTION OF STUDY POPULATION 
11.1 Population Base 
Any opioid-dependent subject about to undergo complete or partial opioid withdrawal and 
could benefit for a minimum of a 7-day treatment with lofexidine will be eligible for the 
study.  Entry into this study is open to both men and women and to all racial and ethnic 
subgroups.  An attempt will be made to include at least 25% female subjects, a mix of 
ethnicities reflecting the distribution in the local geographic regions of the study sites, and a 
minimum of 50 subjects each on methadone or buprenorphine maintenance treatment.  
Subjects will be recruited from a variety of sources, including subjects seeking treatment for 
opioid dependence via referrals from local treatment providers, word of mouth among 
subjects themselves also seeking treatment, and advertising in the local media.  Recruitment 
advertisements will be approved by each site’s Institutional Review Board (IRB). 
Potential subjects may be accepted for screening after the nature and purpose of the 
investigation have been explained to them and after they have voluntarily given written 
informed consent (see Section 16.4). 
11.2 Study Entrance Requirements 
11.2.1 Inclusion Criteria 
To be eligible for participation, subjects must meet all of the following criteria: 
1. Be able to verbalize understanding of the consent form, able to provide written 
informed consent, and verbalize willingness to complete study procedures. 
2. Be male or female at least 18 years of age. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 25


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 25 of 120 
3. Have current dependence, according to the Mini International Neuropsychiatric 
Interview (M.I.N.I.) [18, 19], on any opioid (including methadone and buprenorphine 
maintenance treatment). 
4. Be seeking treatment for partial or total withdrawal from current opioid and expected, 
as determined by the Principal Investigator, to benefit from lofexidine treatment for at 
least 7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This can include a 
variety of clinical situations where opioid withdrawal illness is likely to occur.  
Examples include: 
 abrupt and total withdrawal (including from methadone and buprenorphine); 
 agonist-assisted total withdrawal; 
 dose reduction of maintenance treatment (e.g., methadone, buprenorphine); and 
 transition from an opioid agonist to naltrexone or buprenorphine maintenance. 
5. Urine toxicology screen positive for opioid(s) relevant to the subject’s withdrawal 
treatment goal (can include methadone and buprenorphine) at Screening. 
6. If female and of childbearing potential, subject must agree to use of one of the 
following methods of birth control: 
 oral contraceptives; 
 patch; 
 barrier (diaphragm, sponge or condom) plus spermicidal preparations; 
 intrauterine contraceptive system; 
 levonorgestrel implant; 
 medroxyprogesterone acetate contraceptive injection; 
 complete abstinence from sexual intercourse; 
 hormonal vaginal contraceptive ring; or 
 surgical sterilization or partner sterile (must have had documented proof). 
11.2.2 Exclusion Criteria 
Subjects who meet any of the following criteria will not be allowed to participate: 
1. Be a female subject who is pregnant or lactating. 
2. Have a very serious medical illness not under control as detailed below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 26


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 26 of 120 
 clinical laboratory tests, including standard lab tests, an infectious disease 
panel for syphilis (subject is excluded if positive for active syphilis as per 
required laboratory tests; see also Section 15.5.4.2)  and hepatitis (positive 
results do not exclude a prospective subject from participation unless there is 
an indication of active liver disease); and 
 tuberculin test (purified protein derivative [PPD]) and/or a chest x-ray (a 
positive PPD result does not exclude a prospective subject from participation, 
but if diagnostic tests [e.g., chest x-ray] indicate that active disease is present, 
the subject will be excluded from participation; see also Section 15.5.4.2). 
 Have active self-reported acquired immune deficiency syndrome (AIDS) or self-
reported human immunodeficiency virus (HIV) positive status and taking 
retroviral medications currently or within the past 4 weeks. 
 Have an unstable psychiatric condition (e.g., suicide risk, per Investigator 
judgment). 
3. Current dependence (based on the M.I.N.I.) on any psychoactive substance 
(excluding caffeine, nicotine, and the subject’s current opioid-dependence agent, 
which can include methadone and buprenorphine, for example, in agonist-maintained 
subjects) that requires detoxification or dose reduction as part of the pre-defined 
individual subject withdrawal treatment goal. 
4. Have participated in an investigational drug study within the past 30 days. 
5. Have history of lofexidine exposure in a prior clinical trial or otherwise. 
6. Abnormal cardiovascular exam at screening, including any of the following: 
 clinically significant abnormal electrocardiogram (ECG) (e.g., second or third 
degree heart block, uncontrolled arrhythmia, or QTcF intervals greater than 
450 msec for males and greater than 470 msec for females); 
 resting pulse less than 55 bpm or symptomatic bradycardia; 
 resting systolic blood pressure less than 95 mmHg or symptomatic hypotension; 
 resting diastolic blood pressure less than 65 mmHg; 
 resting blood pressure greater than 155/95 mmHg; or 
 prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the above criteria, the 
value should be confirmed by repeating the measurement (twice, if necessary).  If 2 of 
3 values meet the above criteria, the subject will be excluded from participation. 
7. To avoid drug-drug interactions, subjects requiring the following will be excluded: 
 tricyclic antidepressants, which may reduce the efficacy of imidazoline 
derivatives; and 
 beta-receptor blockers, to avoid the risk of excessive bradycardia. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 27


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 27 of 120 
11.3 Screening Failures 
Screening failures are potential study subjects who provide informed consent and fail 
inclusion and/or exclusion criteria or for other reasons are not allowed to participate.  A 
screening log for all subjects who are screened will be maintained.  The screening log will 
uniquely identify each subject and report whether he or she passed or failed screening, and, if 
he or she did not pass, the reasons for the screening failure. 
12 INVESTIGATIONAL AGENTS 
12.1 Lofexidine Hydrochloride 
Lofexidine hydrochloride is an 2-adrenergic agonist with mild to moderate antihypertensive 
actions.  It has the empirical formula C11H13Cl3N2O representing a molecular weight of 
295.61.  The structural formula is: 
 
Lofexidine hydrochloride is a synthetic product and has the chemical designation of 2-[1-
(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride.  It is a white to 
off-white crystalline powder that is very soluble in water and ethanol.  It is lightly soluble in 
2-propanol and practically insoluble in ether.  Lofexidine hydrochloride melts at 
approximately 126-128°C. 
Lofexidine will be supplied by the Sponsor (USWM) in peach colored tablets containing 
0.2 mg of active medication for oral administration. 
12.2 Dispensing Investigational Agent 
Lofexidine will be packaged and distributed through the pharmacy coordinating center 
(Sharp).  Lofexidine tablets will be supplied in uniquely-identified 80-count bottles.  During 
in-clinic treatment, lofexidine doses will be dispensed directly from the 80-count bottles, 
whereas for outpatient treatment doses will be dispensed by the study pharmacist as 
determined clinically appropriate by the Principal Investigator or designee to the subject in 
individual prescription bottles.  One to 2 days of medication may be dispensed at each daily 
clinic visit to accommodate flexible scheduling (e.g., day and a half worth of medication to 
supply subject from one morning to the next afternoon depending on availability for clinic 
visit).  The site will maintain a dispensing log for each bottle and document the number of 
tablets dispensed to each subject along with the number of tablets returned, if any, by the 
subject at each outpatient visit.  Returned tablets will not be re-dispensed to future subjects. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 28


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 28 of 120 
All study medication will be dispensed by the site pharmacist or designee. 
12.3 Blinding Plan 
This is an open-label study. 
12.4 Labeling 
The investigational agent, lofexidine, will be packaged in labeled bottles (80 count pills) and 
during the outpatient portion of the study dispensed to subjects in labeled prescription bottles 
(i.e., redispensing container).  The product label will include the sponsor’s name, protocol 
number, the number of tablets in the bottle, address, 24-hour emergency phone number, and 
the following statement – “Caution: New Drug – Limited by Federal Law to Investigational 
Use.” 
During outpatient treatment (Days 4-14), sites may dispense 1 to 2 days of medication at 
each daily clinic visit to accommodate flexible scheduling for use in an outpatient setting 
(e.g., day and a half worth of medication to supply subject from one morning to the next 
afternoon depending on availability for clinic visit).  In such cases, the redispensing container 
will include a subject label, supplied by the study site, and will include the following 
information: 
 Principal Investigator’s name and number, 
 Subject number, 
 Date of dispensing, 
 Directions for use, 
 Drug name / dose or protocol number, 
 Number of pills dispensed, 
 Sponsor’s name, and 
 For Investigational Use Only. 
12.5 Storage 
The investigational agent, lofexidine, will be stored at 68-77°F in a secure location at the 
dispensing pharmacy or site.  Temperature of the investigational agent will be maintained at 
68-77°F during transport.  Temperature of the investigational agent will be monitored during 
storage and transport.  Temperature excursions will be reported to the Sponsor and the 
Sponsor will determine if the investigational agent is fit for use. 
12.6 Record of Administration 
Accurate recording of all investigational agent received, dispensed, administered, and 
returned will be maintained by study site personnel.  During outpatient treatment 
(Days 4-14), subjects are to record doses taken in his/her subject diary. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 29


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 29 of 120 
12.7 Used/Unused Supplies 
Unused investigational agent will be retained at the participating sites to enable a full 
investigational drug inventory by the sites’ respective monitor.  If any investigational agent is 
lost or damaged, its disposition should be documented.  The Sponsor will provide 
instructions to return the unused study drug to the pharmacy coordinating center periodically 
throughout the study (following monitor review) or at the end of the study for proper 
destruction in accordance with local and federal regulations. 
12.8 Contraindications 
Clonidine is specifically prohibited in this study. 
To avoid drug-drug interactions, lofexidine should not be administered concurrently with: 
 
tricyclic antidepressants – may reduce the efficacy of imidazoline derivatives; and 
 
beta-receptor blockers – the combination of lofexidine and beta-receptor blockers 
should be used with caution to avoid the risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug therapy and appropriate caution 
is warranted in subjects on such therapy.  The Principal Investigator may need to lower the 
subject’s antihypertensive dose during the study. 
Lofexidine should generally not be administered concurrently with alcohol, sedatives, and 
anesthetics as these may interact with lofexidine and enhance its central sedative effects. 
13 TREATMENT PLAN 
13.1 Investigational Agent 
All subjects in this study will receive lofexidine, as described in Section 13.2. 
13.2 Dose Administration 
13.2.1 Administration of Doses 
Lofexidine administration should be initiated in concurrence with the change in opioid dose 
which is anticipated to elicit withdrawal symptoms (e.g., first day of dose reduction, or first 
day of abrupt cessation) or on the first day of emergence/anticipated emergence of such 
symptoms as determined at the Investigator’s discretion.  Details regarding the timing of 
lofexidine therapy initiation relative to change in opioid dose and onset/expected onset of 
symptoms should be captured in the source.  All subjects will take lofexidine orally for 
7 days, starting on Day 1 at a dose of 3.2 mg per day (0.8 mg QID), with lowering of the 
dose allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the subject’s 
individual treatment goal and response per clinical judgment of the Principal Investigator.  
The subject’s dose may be changed back to 3.2 mg/day, per Principal Investigator judgment, 
but in no case is the dose of lofexidine to exceed 3.2 mg/day (or a single dose of 0.8 mg).  
Supporting rationale for any dose changes must be recorded in the subject’s source 
document. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 30


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 30 of 120 
All subjects will receive all 4 doses of lofexidine in a clinic setting for the first 3 days 
(Days 1-3) and then, per clinical judgment of the Principal Investigator, subjects can continue 
to receive lofexidine doses in a clinic setting or can be treated outside of the clinic 
(outpatient) for the remaining 4 days of mandatory lofexidine treatment (Days 4-7).  Note 
that the decision to allow outpatient treatment should take into account the subject’s 
sensitivity to the hypotensive effects of the study medication (as observed over Days 1-3) and 
the subject’s potential for noncompliance.  Furthermore, the rationale for the decision to 
continue treatment through either an in-clinic or outpatient setting must be documented in the 
subject’s source document.   
During in-clinic treatment, subjects must take lofexidine within a 1-hour window, 30 minutes 
before or after 8 AM and within a 30-minute window, 15 minutes before or after 1 PM, 
6 PM, and 11 PM, with the actual date and time of each dose recorded in the subject’s source 
document and in the eCRF.  For subjects receiving outpatient treatment (elective) on 
Days 4-7 and those continuing optional lofexidine treatment in an outpatient setting for up to 
an additional 7 days (Days 8-14), prescribed dosing will remain on the same QID schedule 
(8 AM, 1 PM, 6 PM, 11 PM) with compliance assessed at the next day’s clinic visit by pill 
count, subject report of dosing in diary (Appendix 3), and a fingerprick blood sample to 
assess plasma lofexidine concentrations.  Note that if the subject is receiving outpatient 
treatment, he/she is required to take a dose of lofexidine in the clinic at each daily clinic visit. 
Optional Outpatient Treatment (Days 8-14) 
Per Principal Investigator judgment, subjects can continue lofexidine treatment on an 
outpatient basis for up to an additional 7 days, per the dose schedule listed below, including 
taking a dose of lofexidine in the clinic at each daily clinic visit.  The rationale for the 
decision to continue lofexidine treatment must be documented in the subject’s source 
document.  Note that lofexidine dosing may be stopped at any time during Days 8-14.  No 
subject will receive lofexidine for more than 14 days total in this study. 
 
If Dose Regimen on Day 7 is 
If Dose Regimen on Day 7 is 
Day 
3.2 mg/day (0.8 mg QID) 
2.4 mg/day (0.6 mg QID) 
8 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
9 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
10 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
11 
1.6 mg/day (0.4 mg QID) 
0.8 mg/day (0.2 mg QID) 
12 
1.6 mg/day (0.4 mg QID) 
0.8 mg/day (0.2 mg QID) 
13 
0.8 mg/day (0.2 mg QID) 
0.8 mg/day (0.2 mg QID) 
14 
0.8 mg/day (0.2 mg QID) 
0.8 mg/day (0.2 mg QID) 
 
Note:  In order to prevent dehydration from opioid withdrawal, increased fluid intake will be 
encouraged from the beginning of the study. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 31


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 31 of 120 
13.2.2 Dose Hold Criteria 
Study medication will be held if pre-dose vital signs meet any of the criteria listed below (see 
Section 10.4 for details on repeat confirmatory requirements). 
Resting (sitting [or recumbent if necessary because of an AE]) 
 
Systolic blood pressure <90 mmHg and >20% below screen value; 
 
Diastolic blood pressure <50 mmHg and >20% below screen value; 
 
Pulse <50 bpm and >20% below screen value; or 
 
Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness). 
Orthostatic (after standing for 3 minutes) 
 
Systolic blood pressure diastolic blood pressure, or pulse >25% below 
recumbent values. 
During outpatient treatment, if the subject experiences symptoms of hypotension and/or 
bradycardia (see below), he/she should call the study site and the site should instruct the 
subject on whether the next dose should be delayed, skipped, or he/she should be seen in the 
clinic.  The subject should record this information in the subject diary (Appendix 3). 
 marked dizziness 
 fainting (especially when standing from a sitting or lying position) 
 light headedness 
 Fatigue 
 Weakness 
 shortness of breath 
 chest pains 
 easily tiring during physical activity 
 confusion or memory problems 
 blurred vision 
 nausea 
 cold, clammy pale skin 
 rapid shallow breathing 
 depression 
 thirst 
All instances of dose-holds must be clearly documented in the subject’s source document and 
dosing eCRF, and the event causing the dose hold should be recorded on the AE or SAE 
eCRF, as applicable. 
13.2.3 Discontinuation Criteria 
A subject will be discontinued from the study if any of the criteria listed below are met (see 
Section 10.4 for details on repeat confirmatory requirements).  All instances should be 
recorded in the subject’s source document and AE or SAE eCRF, as applicable. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 32


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 32 of 120 
 
Resting systolic blood pressure <70 mmHg; 
 
Resting diastolic blood pressure <40 mmHg; 
 
Resting pulse <40 bpm; 
 
QTcF >500 msec1 or >25% above screen value for both males and females; or 
 
Syncope. 
Additional discontinuation criteria based on cardiovascular events are: 
 New onset of clinically significant abnormal ECG per Investigator judgment 
(e.g., second or third degree heart block or uncontrolled arrhythmia, prolonged 
QTcF interval). 
 Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or 
fluids). 
 Single occurrence of symptomatic bradycardia (as assessed by Principal 
Investigator/study physician/assigned staff, regardless of blood pressure) associated 
with chest pain, shortness of breath, or decreased level of consciousness. 
 Persistent hypertension – resting blood pressure ≥185/110 mmHg recorded on 3 
separate occasions taken at least 5 minutes apart AND within a 1-hour time period.  If 
2 of 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. 
 Medical Intervention for Cardiovascular Event:  Any medical intervention 
(nonmedication or medication inclusive) used for the treatment of any cardiovascular 
event, with the exception of a positional intervention in subjects displaying 
hypotension. 
 Any other clinically significant cardiovascular signs or symptoms that would place the 
subject at risk. 
 Subject misses more than a total of 6 doses during Days 1-7. 
13.3 Treatment Compliance 
All subjects will receive all 4 doses of lofexidine in a clinic setting for the first 3 days of 
lofexidine treatment (Days 1-3) and then, per clinical judgment of the Principal Investigator, 
subjects can continue to receive lofexidine doses in a clinic setting or can be treated outside 
of the clinic (outpatient) for the remaining 4 days of mandatory lofexidine treatment 
(Days 4-7).  Per Principal Investigator judgment, subjects can continue lofexidine treatment 
beyond Day 7 on an outpatient basis only for up to an additional 7 days (Days 8-14).  No 
subject will receive lofexidine for more than 14 days total.  In an in-clinic setting, each dose 
will be observed by study staff and hand and mouth checks will be performed.  In an 
                                                 
1 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval.  
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 33


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 33 of 120 
outpatient setting, self-dosing compliance will be evaluated at the next day’s clinic visit by 
pill count, subject report of dosing in diary (Appendix 3), and a fingerprick blood sample to 
assess plasma lofexidine concentrations.  Subjects will be instructed to call the Principal 
Investigator’s office before taking the next dose of study medication if they notice any 
symptoms of hypotension and/or bradycardia (see list in Section 13.2.2), especially when 
standing from a sitting or lying position.  The study physician or assigned staff will 
determine if the next dose should be delayed, skipped, or the subject should be seen.  Any 
change in prescribed dosing will be recorded and confirmed also by pill count and subject 
report at the next visit. 
13.4 Nicotine Replacement Therapy 
Subjects may be permitted to smoke during their in-clinic participation in study based on 
individual site policy.  If they usually use tobacco products, they will be offered and 
encouraged to use nicotine replacement therapy (patch, gum, inhaler, or nasal spray) while 
they are in the in-clinic facility to treat their nicotine withdrawal symptoms.  If smoking is 
permitted by a participating site, smoking breaks outside of the in-clinic facility must be 
constantly observed and supervised. 
The estimated total number of tobacco products used by subjects per day during in-clinic 
treatment will be recorded in the subject’s source document and on the eCRF. 
14 STUDY PROCEDURES 
14.1 Subject Recruitment and Consent 
Interested subjects, who respond to recruitment materials and are available to stay for the 
mandatory 3-day in-clinic treatment part of the study and available for participation in either 
an in-clinic or outpatient setting for 4 additional days (total commitment of 7 days), will be 
scheduled to meet with a qualified investigative staff member and receive an explanation of 
the study purpose and requirements in lay language.  During the initial interview, the 
interviewer should not ask questions in a manner that reveals the eligibility criteria for study 
entry. 
If still interested after receiving an explanation of the study, a qualified investigative site staff 
member will review the study informed consent form with subjects, and subjects will be 
given an opportunity to review on their own, inquire about, and sign the informed consent 
form (see Section 16.4).  The subject will then be given a copy of the signed consent form.  
After that, subjects will be given a subject number and proceed to the screening phase of the 
study.  Screening assessments must be completed within a 9-day time period, but can be 
completed as early as the first screening day.  At no time during the screening process should 
individuals be given information regarding inclusion or exclusion criteria.  When individuals 
are evaluated, questions should be asked in a way that the criteria are not discernible. 
Any subject who has difficulty understanding the information contained in the consent form 
will reread the misunderstood portion(s) of the consent and discuss with a research staff 
member until s/he shows complete understanding of the information in the consent form, and 
may thus give full consent.  Research staff will work closely with the subject in an effort to 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 34


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 34 of 120 
help them understand the requirements of their participation.  Subjects with literacy problems 
will be assisted to the extent possible. 
Any subject who is unable to demonstrate understanding of the information contained in the 
informed consent will be excluded from study participation and assisted in finding other 
sources of treatment at the subject’s sole expense.  Subjects who are excluded, or who 
decline participation, may be rescreened at a later time, although at least 30 days must occur 
between screenings.  Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
14.2 Screening 
Screening assessments will be conducted as shown in Table 1 (Section 15).  The screening 
period will last up to 9 days during which the subjects must satisfy the eligibility criteria and 
complete all required screening assessments. 
14.3 Treatment Phase 
14.3.1 Days 1-3 (Mandatory In-clinic) 
After a potential participant has completed all screening assessments and has met all 
eligibility criteria to participate in the study, the Principal Investigator or study coordinator 
will arrange for admission to the hospital or clinic in the evening (Day -1) or early morning 
(Day 1) before study drug administration on Day 1.  After all Baseline requirements have 
been completed (Section 15.2), subjects will receive their first dose of lofexidine during the 
8 AM dosing window on Day 1.  Subjects will be dosed 4 times daily from Day 1 through 
Day 3 at 8 AM, 1 PM, 6 PM, and 11 PM.  Vital signs will be recorded within 30 minutes 
before every dose and 3.5 hours (±15 minutes) after the 8 AM, 1 PM, and 6 PM dose.  
12-lead ECGs will also be collected before the first dose on Day 1 (8 AM) and 3.5 hours 
(±15 minutes) after dosing.  Note that should a second or third measurement be required with 
waiting between measurements, the timing of the measurement will not be considered a 
protocol deviation (i.e., outside the protocol-specified window).  Other clinical assessments 
will be gathered between 11:00 AM and noon each day (see a complete list of assessments in 
Table 1).  These clinical assessments are described in detail in Sections 15.3.5 and 15.5. 
14.3.2 Days 4-7 (In-clinic/Outpatient) 
Per clinical judgment of the Principal Investigator, subjects can continue to receive 
lofexidine treatment in a clinic setting or can be treated outside of the clinic (outpatient) for 
the remaining 4 days of mandatory lofexidine treatment (Days 4-7).  All subjects receiving 
lofexidine treatment on an outpatient basis will be required to take a dose of lofexidine in the 
clinic at each daily clinic visit, with required clinical assessments performed before and after 
dosing as detailed in Table 1.  Subjects not requiring extended lofexidine treatment can be 
discharged from the study on Day 7 after receipt of at least one dose of study drug and after 
all end-of-study procedures have been completed (see Section 15.3.4). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 35


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 35 of 120 
14.3.3 Days 8-14 (Outpatient Only) 
Per Principal Investigator judgment, subjects can continue lofexidine treatment on an 
outpatient basis for up to an additional 7 days.  Note that lofexidine dosing may be stopped at 
any time during Days 8-14.  No subject will receive lofexidine for more than 14 days total in 
this study.  Subjects will be required to return to the clinic daily before a scheduled dose for 
clinical assessments (see a complete list of assessments in Table 1). 
14.4 Subject Reimbursement 
All compensation will be described in the informed consent form used by each site and 
approved by the site’s or central IRB 
. 
14.5 Study Discontinuation 
14.5.1 Subject Discontinuation 
A subject can withdraw his/her consent for participation in the study at any time without 
prejudice.  The Principal Investigator may discontinue a subject if s/he deems it clinically 
appropriate or for any reason.  Additionally, the Principal Investigator must discontinue a 
subject for any of the following reasons: 
1. Cardiovascular events (see Section 14.5.2). 
2. Abnormal vital signs or ECG meeting criteria in Section 13.2.3. 
3. Serious medical problem thought to be related or unrelated to the study medications. 
4. Intercurrent illness or medical complications that, in the opinion of the Principal 
Investigator, preclude safe administration of study medications. 
5. Alcohol or other sedative/hypnotic withdrawal signs and symptoms developing 
following enrollment into the study (Days 1-3). 
6. Requiring therapy with an exclusionary drug. 
7. Lack of compliance with protocol and/or unit procedures. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 36


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 36 of 120 
Subjects who are removed from study treatment because of AEs or SAEs will be followed 
until they are medically stabilized to the satisfaction of the study physician or assigned staff 
(see Sections 15.5.1, 16.7, and 16.8).  Appropriate safety evaluations will continue to be 
collected until the subject is discharged from the treatment center or the maximum 14-day 
treatment period has expired.  This stabilization can include medically supervised opioid 
withdrawal (involving behavioral therapy, rescue opioid medications, and/or non-opioid 
pharmacotherapy) or referral to an appropriate methadone or buprenorphine therapy 
program. 
Any subject that discontinues from the study, regardless of the reason, will be requested to 
complete all Study Discontinuation/End of Study assessments and procedures (see Table 1). 
The reason for discontinuation will be recorded on the end of study form provided in the 
subject’s eCRF.  Once discontinued, subjects may not re-enter the study.  Discontinued 
subjects will not be replaced. 
Study subjects discontinued from the protocol secondary to a medical or psychiatric concern 
deemed to be unrelated to lofexidine therapy will be referred, at the subject’s sole expense, 
for appropriate treatment, and may include psychological and lifestyle counseling, support 
groups, pharmacological, and medical treatment.  Subjects will be asked to sign a general 
consent for the release of information to the referred healthcare provider.  Study staff may 
request transportation for emergency treatment of a subject if medically appropriate (e.g., for 
acutely psychotic or suicidal subjects). 
14.5.2 Cardiovascular Events Requiring Subject Discontinuation From Study 
Subjects should be discontinued from the study for any of the reasons listed below, and the 
event should be recorded in the subject’s eCRF as an AE or SAE (see Sections 15.5.1, 16.7, 
and 16.8) and the subject followed until medically stabilized to the satisfaction of the study 
physician. 
1. New onset of clinically significant abnormal ECG per Investigator judgment 
(e.g., second or third degree heart block or uncontrolled arrhythmia, prolonged QTcF 
interval2). 
2. Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or 
fluids). 
3. Single occurrence of symptomatic bradycardia (as assessed by Principal 
Investigator/study physician/assigned staff, regardless of blood pressure) associated 
with chest pain, shortness of breath, or decreased level of consciousness. 
                                                 
2 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 37


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 37 of 120 
4. Persistent hypertension – resting blood pressure ≥185/110 mmHg recorded on 3 
separate occasions taken at least 5 minutes apart AND within a 1-hour time period.  If 
2 of 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. 
5. Medical Intervention for Cardiovascular Event:  Any medical intervention 
(nonmedication or medication inclusive) used for the treatment of any cardiovascular 
event, with the exception of a positional intervention in subjects displaying 
hypotension. 
6. Any other clinically significant cardiovascular signs or symptoms that would place the 
subject at risk. 
14.5.3 Trial Discontinuation 
The Sponsor (USWM) has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
 the incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects; 
 subject enrollment is unsatisfactory;  
 data recording is inaccurate or incomplete; and 
 the safety database is judged to be sufficient, i.e., a minimum of 300 subjects (across 
this protocol and earlier lofexidine clinical studies expected to meet FDA safety 
database requirements) have been treated with clinically relevant doses of lofexidine for 
a minimum of 7 days. 
14.6 Concomitant Therapy 
If the individual withdrawal treatment goal requires a specific concomitant medication 
(e.g., agonist-assisted total withdrawal, transition to buprenorphine or naltrexone, dose 
reduction of maintenance therapy), that concomitant medication is allowed.  At no time are 
clonidine, tricyclic antidepressants, and beta-receptor blockers allowed (see Section 12.8). 
Other concomitant medications or therapies are permitted throughout the study in either an 
in-clinic or outpatient setting, as clinically warranted.  The following medications were found 
to be useful in earlier lofexidine efficacy/safety studies and, for consistency, the Principal 
Investigator/study physician/assigned staff may consider their use in this study as 
appropriate. 
1. Guaifenesin (for cough). 
2. Alumina, Magnesia, and Simethicone (for emesis and nausea). 
3. Dioctyl sodium sulfosuccinate and psyllium hydrocolloid suspension (for constipation). 
4. Bismuth sulfate (Pepto-Bismol®) and loperamide (Imodium®) (for diarrhea). 
5. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (for headache, 
muscle aches, or other discomfort. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 38


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 38 of 120 
6. Zolpidem, trazadone, and other benzodiazepines (for insomnia, depression, anxiety).   
The Principal Investigator/study physician/assigned staff should contact the Sponsor’s 
Medical Monitor regarding any questions on concomitant medications. 
The site should document in source any symptom that requires administration of any 
concomitant medication as an AE (see Section 15.5.1). 
All medications taken will also be recorded in source and on the subject’s eCRF along with 
dose, dates of administration, and reason for use. 
15 CLINICAL EVALUATIONS 
A detailed Schedule of Study Assessments is provided in Table 1. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 39


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 39 of 120 
Table 1. Schedule of Study Assessments 
 
 
Screening 
 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
Activity 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
End of Study* 
Informed Consent Signed 
X 
 
 
 
 
 
Subject Number Assigned 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X (b) 
 
 
 
 
Prior Medication History 
Past 30 days 
X (b) 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and Smoking History 
X 
 
 
 
 
 
Mini-International Neuropsychiatric Interview  
X 
 
 
 
 
 
Infectious Disease Assessments (c) 
X 
 
 
 
 
 
Chest X-Ray (c) 
X 
 
 
 
 
 
Pregnancy Test (d) 
X 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
Complete Physical Exam 
X 
X (b) 
X (e) 
As needed 
As needed 
X 
Admission to In-clinic Facility 
 
X (f) 
 
 
 
 
Study Medication Administration 
 
 
X (QID) 
X (QID) (g) 
Optional 
 
Medication Compliance 
 
 
X 
X 
X 
X 
Study Medication Taper 
 
 
 
 
X 
 
Discharge from In-clinic Facility 
 
 
 
Variable, but by Day 7 
 
 
Clinic Visit 
 
 
 
Daily if outpatient 
Daily 
 
Issue Subject Diary 
 
 
 
Daily if outpatient 
Daily 
 
12-Lead Electrocardiogram (duplicate) 
X (h) 
X (i) 
X (i) 
 
 
X (j) 
Urine Drug Screen (k) 
X 
X 
X 
X 
X 
X 
Vital Signs (Sitting/Recumbent & Standing BP 
and pulse; respiration; and temperature) 
X 
X 
X (l) 
X (l) (m) 
X (m) 
X 
Clinical Laboratory Tests (hematology, 
chemistry, urinalysis) 
X 
As needed 
As needed 
As needed 
As needed 
X 
Adverse Events Assessment 
 
 
X 
X 
X 
X 
C-SSRS Baseline Version 
 
X 
 
 
 
 
C-SSRS Since Last Visit Version 
 
 
X (n) 
X (n) 
X (n) 
X 
Short Opiate Withdrawal Scale of Gossop (o) 
 
X 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) (o) 
 
X 
X 
X 
X 
X 
Fingerprick Blood Sample 
 
 
X (p) 
X (q) 
X (p) (q) 
X (p) 
Concomitant Medications Assessment 
 
 
X 
X 
X 
X 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 40


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 40 of 120 
Table 1. Schedule of Study Assessments 
 
 
Screening 
 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
Activity 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
End of Study* 
Define Subject-Specific Withdrawal 
Treatment Goal 
X 
 
 
 
 
 
Assessment of Completion of Pre-defined 
Withdrawal Treatment Goal (r) 
 
 
X  
X 
X 
X 
Telephone Follow Up Contact 
 
 
 
 
 
X (s) 
Abbreviations:  BP = blood pressure, C-SSRS = Columbia Suicide Severity Scale, PK = pharmacokinetic, PPD = purified protein derivative, QID = 4 times daily 
* 
The study discontinuation/end of study assessments/procedures should always be done when subject exits from the study. 
(a) The Baseline period is the morning of admission, before dosing. 
(b) This form is to be updated at Baseline. 
(c) A chest x-ray is required only if a PPD skin test for tuberculosis is not done, the current PPD is positive, or if a past PPD was positive. 
(d) The urine sample collected on the first day of screening will be divided into two aliquots.  One sample will be sent to the central lab 
for 
urinalysis and the other sample will be used for urine drug screening and immediate “dipstick” analysis of pregnancy (females only). 
(e) A complete physical exam will be done on Day 1 (3-4 hours after first dose) and as clinically warranted. 
(f) Subjects may be admitted to the hospital or clinic in the evening (Day -1) before study drug administration on Day 1. 
(g) Per Investigator judgment, subjects can be discharged from the study after receipt of at least one dose of study drug on Day 7 and after completion of all end-of-study procedures. 
(h) Baseline 12-lead electrocardiograms (ECGs) will be done on one day during the screening period at 8 AM (or as close to 8 AM as possible) and at 11:30 AM.  Note that a time 
delay for the 8 AM ECG will not be considered a protocol deviation, but that the second ECG should be taken 3.5 hours after the first ECG. 
(i) 12-lead ECGs (duplicate) before dosing on Day 1 at 8 AM and 3.5 hours (± 15 minutes) after dosing. 
(j) 12-lead ECGs (duplicate) before subject’s last dose and 3.5 hours after dosing (or as close to this time as possible) or, if applicable, at discontinuation from the study.  
(k) Urine drug screen will be done every day in an in-clinic setting to monitor for contraband and every day in an outpatient setting to monitor illicit drug use.  
(l) During in-clinic treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured before every 
dose and 3.5 hours after study medication administration at 8 AM, 1 PM, and 6 PM; respiration and temperature before 8 AM dose only. 
(m) During outpatient treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured before an in-
clinic dose of lofexidine each day and 3.5 hours after dosing on Days 4-13 and once before any dose on Day 14 and at the End of Treatment/Study Discontinuation visit.  Oral 
temperature and respiration are not required measurements during outpatient treatment. 
(n) C-SSRS will be completed 3.5 hours after the first dose (8 AM) during in-clinic treatment or once daily before an in-clinic dose of lofexidine during outpatient treatment. 
(o) During in-clinic treatment, effectiveness scales will be completed once daily:  the Short Opiate Withdrawal Scale of Gossop 3.5 hours (±10 minutes) after the first dose of study 
medication followed by COWS, and the assessment of completion of pre-defined withdrawal treatment goal.  Effectiveness scales will be completed daily before an in-clinic dose 
of lofexidine during outpatient treatment. 
(p) A fingerprick blood sample for PK analysis will be collected concurrently with each scheduled ECG. 
(q) A fingerprick blood sample will be collected during outpatient treatment when the subject reports to the clinic each day (before next scheduled dose) for analysis of plasma 
lofexidine concentration to monitor compliance. 
(r) This form is to be completed by the Principal Investigator after completion of the SOWS-Gossop and COWS. 
(s) A follow-up telephone contact will be attempted 30 days after the subject’s last dose and will include an adverse event evaluation and an evaluation of the subject’s current 
treatment status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, buprenorphine, or naltrexone program). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 41


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 41 of 120 
15.1 Screening Assessments 
Subjects seeking treatment for opioid dependence at one of the study sites will be screened 
for study enrollment.  Screening assessments must be completed within a 9-day time period.  
The screening visit will have a visit window of ±2 days.  Subjects will not be out of 
compliance if visit windows extend because of extraordinary events that make it impossible 
for subjects to complete a screening within the ±2-day window (e.g., holidays, vacations, 
personal emergencies).  Determination of the maximum visit window deviation is, however, 
at the discretion of the medical monitor.  Written informed consent must be obtained from all 
study subjects before initiation of any study procedures. 
The following screening assessments must be completed during screening after determining 
eligibility and written informed consent is obtained:  height; weight; vital signs 
(sitting/standing blood pressure and pulse; respiration; and temperature); blood collection for 
standard clinical safety laboratory assessments (including hematology and biochemistry); 
urine sample for confirmatory drug testing, urinalysis, and pregnancy assessment (if female); 
and infectious disease assessment (see Section 15.5.4.2) and a chest x-ray if a past PPD skin 
test for tuberculosis was positive. 
The urine sample collected will be divided into two aliquots:  one sample will go to the 
central lab 
 for urinalysis; the other sample will be used 
for “dipstick” analysis of pregnancy and qualitative drug screening. 
The assessments listed below must also be performed during screening. 
 
12-lead ECGs (in duplicate) will be done on one day during the screening period at 
8 AM (or as close to 8 AM as possible) and at 11:30 AM.  Note that a time delay for 
the 8 AM ECG will not be considered a protocol deviation, but that the second ECG 
should be taken 3.5 hours after the first ECG.  
 Medical and smoking/alcohol history. 
 Complete physical examination. 
 Mini International Neuropsychiatric Interview (M.I.N.I.) [18, 19].  The M.I.N.I. will be 
performed once at screening only to (1) establish that each potential subject is opioid-
dependent (inclusion criterion #2) and (2) determine the absence of major psychiatric 
disorders (exclusion criterion #3). 
 Prior medications will be recorded to capture all medications taken in the past 30 days. 
 All opioids of abuse the subject has used will be recorded. 
In addition, each subject will have a short-term (within the 14-day study period) withdrawal 
treatment goal defined according the criteria below (see Appendix 4 for further details on this 
assessment). 
 Abrupt and total withdrawal (e.g., quitting heroin abruptly and totally), including 
whether naltrexone maintenance will be initiated as part of the short-term treatment 
goal. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 42


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 42 of 120 
 Agonist-assisted total withdrawal (e.g., quitting heroin with methadone or other 
agonist, including buprenorphine, given as needed to alleviate symptoms), including 
whether naltrexone maintenance will be initiated as part of the short-term treatment 
goal. 
 Step-down/dose reduction resulting in partial withdrawal (e.g., lowering methadone or 
buprenorphine maintenance dose or chronic pain medication dose). 
 Transition (e.g., transitioning from heroin or methadone to buprenorphine 
maintenance). 
15.2 Baseline Assessments 
The Baseline period is the morning of admission to the study, before dosing.  Prospective 
subjects who meet all eligibility criteria must be admitted to the study in time to give the first 
dose of study medication at 8 AM (±30 minutes). 
The assessments listed below will be performed during the Baseline period before dosing. 
 SOWS-Gossop. 
 COWS. 
 Vital signs (resting [sitting or recumbent, if applicable]) and standing blood pressure 
and pulse; respiration, temperature) measurements. 
 Repeat pregnancy assessment (by “dipstick”), if female. 
 Repeat urine drug screen (by “dipstick”). 
 Update Inclusion/Exclusion Criteria form to reflect Baseline assessments.  
 Update prior medication form to capture any new medications since screening. 
 Update complete physical exam form to capture any new physical findings since 
screening. 
 Columbia Suicide Severity Rating Scale (C-SSRS) (Baseline version; Appendix 5). 
 12-lead ECGs (in duplicate) before the first dose on Day 1 at 8 AM. 
15.3 Assessments During Treatment 
15.3.1 Days 1-3 (Mandatory In-clinic) 
The assessments or procedures listed below will be performed daily (unless otherwise 
specified) on Days 1-3 (see Section 15.3.4 for assessments/procedures required for 
discontinuation from the study). 
 Study medication administration QID at 8 AM, 1 PM, 6 PM, and 11 PM. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 43


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 43 of 120 
 Effectiveness assessments at estimated time of maximum plasma concentration (Tmax, 
i.e., 3.5 hours after the first daily dose) including: 
 SOWS-Gossop; and 
 COWS. 
 Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
 Concomitant medication assessment. 
 Vital signs including blood pressure and pulse at rest (sitting [or recumbent if necessary 
because of an AE]) and standing (if able) before every dose and 3.5 hours after 
administration of study medication at 8 AM, 1 PM, and 6 PM (7 times per day); 
respiration and temperature before 8 AM dose only. 
 Continuous monitoring for AEs. 
 12-lead ECGs (in duplicate) before the first dose on Day 1 at 8 AM and 3.5 hours 
(±15 minutes) after dosing.  
 A fingerprick blood sample for PK analysis will be collected concurrently with each 
scheduled ECG. 
 Clinical laboratory tests as clinically warranted. 
 Complete physical examination 3 to 4 hours after dosing on Day 1 and as clinically 
warranted. 
 C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours after the first dose (8 AM) 
on Days 1-3. 
 A qualitative urine drug screening (by on-site use of “dipsticks”) will be done every 
day to monitor for contraband. 
15.3.2 Days 4-7 (In-clinic/Outpatient) 
The assessments or procedures listed below will be performed daily (unless otherwise 
specified) on Days 4-7 (see Section 15.3.4 for assessments/procedures required for 
discontinuation from the study). 
 Study medication administration QID at 8 AM, 1 PM, 6 PM, and 11 PM.  Note that if 
subject is receiving outpatient treatment, he/she is required to take a dose of lofexidine 
in the clinic at each daily clinic visit. 
 SOWS-Gossop 3.5 hours after the first daily dose during in-clinic treatment; once daily 
before an in-clinic dose of lofexidine during outpatient treatment. 
 COWS 3.5 hours after the first daily dose during in-clinic treatment; once daily before 
an in-clinic dose of lofexidine during outpatient treatment. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 44


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 44 of 120 
 Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
 Concomitant medication assessment. 
 Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses if being treated as an outpatient. 
 Vital signs including blood pressure and pulse at rest (sitting [or recumbent if necessary 
because of an AE]) and standing (if able) during in-clinic treatment before every dose 
and 3.5 hours after administration of study medication at 8 AM, 1 PM, and 6 PM 
(7 times per day); respiration and temperature before 8 AM dose only. 
 Vital Signs including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able) during outpatient treatment before 
an in-clinic dose of lofexidine each day and 3.5 hours after dosing.  Note that if the 
subject cannot stay in the clinic for measurement of the 3.5-hour post-dose vital signs 
required on Days 4-7, they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point.  Subjects will also be 
provided a diary (Appendix 3) to record the measurements along with any symptoms of 
hypotension and/or bradycardia (see list in Section 13.2.2) the subject may have 
experienced. 
 A fingerprick blood sample will be collected during outpatient treatment when the 
subject reports to the clinic each day (before next scheduled dose) for analysis of 
plasma lofexidine concentration to monitor compliance. 
 AE assessment. 
 Clinical laboratory tests as clinically warranted. 
 Complete physical examination as clinically warranted. 
 C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours after the first dose (8 AM) 
during in-clinic treatment; once daily before an in-clinic dose of lofexidine during 
outpatient treatment. 
 Qualitative urine drug screening (by on-site use of “dipsticks”) will be done every day 
in an in-clinic setting to monitor for contraband and every day in an outpatient setting 
to monitor for illicit drug use. 
 Daily clinic visits and completion of subject diary for outpatients. 
Subjects not requiring extended lofexidine treatment can be discharged from the study on 
Day 7 after receipt of at least one dose of study drug and after all end-of-study procedures 
have been completed (see Section 15.3.4). 
15.3.3 Days 8-14 (Outpatient Only) 
Study medication is optional on Days 8-14 for subjects continuing to have withdrawal 
symptoms per the Principal Investigator’s judgment.  The assessments and procedures listed 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 45


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 45 of 120 
below will be performed daily (unless otherwise specified) (see Section 15.3.4 for 
assessments/procedures required for discontinuation from the study). 
 Daily clinic visits and completion of subject diary. 
 SOWS-Gossop before an in-clinic dose of lofexidine. 
 COWS before an in-clinic dose of lofexidine. 
 Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
 Concomitant medication assessment. 
 Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses. 
 Vital Signs, including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able) before an in-clinic dose of 
lofexidine and 3.5 hours after dosing on Days 8-13 and once before any dose on 
Day 14.  Note that if subjects cannot stay in the clinic for measurement of the 3.5-hour 
post-dose vital signs required on Days 8-13, they will be given a portable digital blood 
pressure machine for measurement of their vital signs at this required time point.  
Subjects will also be provided a diary (Appendix 3) to record the measurements along 
with any symptoms of hypotension and/or bradycardia (see list in Section 13.2.2) the 
subject may have experienced. 
 AE assessment. 
 Clinical laboratory tests as clinically warranted. 
 Complete physical examination as clinically warranted. 
 C-SSRS (Since Last Visit Version; Appendix 6) before an in-clinic dose of lofexidine. 
 A fingerprick blood sample will be collected during outpatient treatment when the 
subject reports to the clinic each day (before next scheduled dose) for analysis of 
plasma lofexidine concentration to monitor compliance. 
 Qualitative urine drug screening (by on-site use of “dipsticks”) will be done every day 
in an outpatient setting to monitor for illicit drug use. 
15.3.4 Study Discontinuation/End of Study 
Any subject that discontinues from the study, regardless of the reason (see all scenarios listed 
in Section 14.5.1), will be requested to complete all Study Discontinuation/End of Study 
assessments and procedures as listed below after the last dose of study medication. 
 SOWS-Gossop. 
 COWS. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 46


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 46 of 120 
 Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
 Concomitant medication assessment. 
 Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses if not already performed. 
 Vitals signs including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able); respiration; and temperature.  
 AE assessment. 
 12-lead ECGs (in duplicate) before the subject’s last dose and 3.5 hours after dosing (or 
as close to this time as possible). 
 Clinical laboratory tests. 
 Complete physical examination (including body weight). 
 Pregnancy test. 
 Urine drug screen. 
 C-SSRS (Since Last Visit version; Appendix 6). 
15.3.5 30-Day Telephone Follow-up Contact 
A  follow-up telephone contact will be attempted 30 days after the subject’s last dose and 
will include an adverse event evaluation and an evaluation of the subject’s current treatment 
status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, 
buprenorphine or naltrexone program).  Repeated attempts will be made to reach the subject 
(defined as a minimum of 3 telephone calls, followed by sending a letter).  If repeated 
attempts are unsuccessful, this will be recorded in the subject’s source document and eCRF. 
15.4 Effectiveness Assessment Methods 
15.4.1 Assessment of Completion of Pre-Defined Withdrawal Treatment Goal 
The Principal Investigator will indicate if the subject has completed his/her pre-defined 
withdrawal treatment goal (Appendix 4) on Days 1-7 by responding to the following 
question:  “Has the subject’s withdrawal treatment goal been reached?”  Note that, per 
protocol, subjects are required to continue on their dose of lofexidine through Day 7 even 
though the subject may have completed his/her withdrawal treatment goal before Day 7.  
This same assessment will be made at each visit during the 7 days of optional outpatient 
treatment (Days 8-14).  This assessment should be completed after the SOWS-Gossop and 
COWS assessments. 
15.4.2 Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
The SOWS-Gossop [16] will be completed by the subject at baseline, once daily at 3.5 hours 
(± 10 minutes) after the first dose of study medication during in-clinic treatment and once 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 47


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 47 of 120 
daily before an in-clinic dose of lofexidine during outpatient treatment.  Note that at the time 
of each daily evaluation, subjects should consider their symptoms over the last 24-hour 
period or since the last time the subject took this test.  Also, this scale should be completed 
before completion of the COWS. 
The SOWS-Gossop scale assesses subjective symptoms of opioid withdrawal (Appendix 1).  
It is a subject-rated scale consisting of 10 items that are scored on a 4-point scale of 0 = none, 
1 = mild, 2 = moderate, and 3 = severe (minimum score of 0, maximum score of 30) (see 
Table 2 below).  The overall score will be the simple sum of the 10-item scores.  Lower 
observed values in SOWS-Gossop scores indicate a more positive clinical outcome. 
Table 2. 
SOWS-Gossop Scoring Method 
Condition 
Score 
None 
Mild 
Moderate 
Severe 
Feeling Sick 
0 
1 
2 
3 
Stomach Cramps 
0 
1 
2 
3 
Muscle Spasms/Twitching 
0 
1 
2 
3 
Feeling of Coldness 
0 
1 
2 
3 
Heart Pounding 
0 
1 
2 
3 
Muscular Tension 
0 
1 
2 
3 
Aches and Pains 
0 
1 
2 
3 
Yawning 
0 
1 
2 
3 
Runny Eyes 
0 
1 
2 
3 
Insomnia/Problems Sleeping 
0 
1 
2 
3 
Note:  Possible score range = 0 to 30. 
 
15.4.3 Clinical Opiate Withdrawal Scale (COWS) 
The COWS [17] will be used to assess the effectiveness of lofexidine in alleviation of opioid 
withdrawal, and will be completed after the SOWS-Gossop and before the assessment of 
completion of pre-defined withdrawal treatment goal.  It will be completed at baseline 
(before dosing on Day 1), once daily at 3.5 hours after the first dose of study medication 
during in-clinic treatment, and once daily before an in-clinic dose of lofexidine during 
outpatient treatment.  The COWS is a clinician-administered instrument that rates 11 
common opioid withdrawal signs and symptoms (Appendix 2).  These include:  resting pulse 
rate; sweating; restlessness; pupil size; bone or joint aches; runny nose or tearing; 
gastrointestinal (GI) upset; tremor; yawning; anxiety or irritability; and gooseflesh skin.  The 
score for each item reflects the severity of the sign or symptom, and the total scores are 
grouped as mild (5-12 points), moderate (13-24 points), moderately severe (25-36 points), 
and severe (>36 points). 
15.5 Safety Assessment Methods 
15.5.1 Adverse Events 
The occurrence of AEs will be assessed starting at the treatment phase of the protocol 
(i.e., with the first dose of study drug).  Any AE that occurs during screening will be 
recorded in the subject’s Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 48


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 48 of 120 
Adverse events will be assessed and recorded around the same time each day by study staff 
during in-clinic lofexidine treatment.  If an AE requires medical attention, it should be 
reported to a study physician immediately.  A study physician or assigned staff must meet 
with the subject to assess all medical and psychiatric AEs reported by the subject, as well as 
those recorded by other study 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 
physician or assigned staff must review with the subject and assess any AEs unresolved from 
the previous day.  For each daily AE assessment, details will be recorded in the subject’s 
source document and AE eCRF, according to the procedures described in Section 16.7, the 
type of AE and whether it is serious (SAE) or non-serious, severity of each AE, and the 
relationship to the study agent.  These categories are asking for the Principal Investigator or 
physician designee’s best judgment of the severity and relatedness of each AE.  The Principal 
Investigator or physician designee will also record, based on his/her best judgment, whether 
the AE is secondary to opioid withdrawal (see Section 15.5.1.1).  In general, an AE should 
not be marked as withdrawal related AND related to study medication. 
Any study subject with a related AE will be followed 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 be followed 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. 
During outpatient treatment, subjects will be queried about AEs at each daily clinic visit.  All 
subjects will be instructed to contact the study physician or assigned staff if he or she 
experiences any symptoms of hypotension and/or bradycardia (see list in Section 13.2.2) 
(especially on standing from a sitting or lying position) and delay additional lofexidine 
dosing until further instructed. 
All reported AEs will be recorded as described above. 
15.5.1.1 Withdrawal-Related Adverse Events 
The Principal Investigator or physician designee will also record, based on his/her best 
judgment, whether the AE is secondary to opioid withdrawal.  Individual items reported on 
the efficacy scales (i.e., SOWS-Gossop, COWS) do not automatically qualify as a 
withdrawal-related AE unless the subject specifically reports them in response to the non-
leading question (i.e., “How have you been feeling since I saw you last?”).  In the event a 
subject reports “withdrawal” or a similar event encompassing a collection of potential 
withdrawal symptoms, the subject should be asked to elaborate so that each specific 
symptom can be recorded on the AE eCRF.  In general, an AE/SAE should not be marked as 
withdrawal related AND related to study medication. 
15.5.2 Vital Signs 
Vital signs (sitting/standing systolic and diastolic blood pressure, pulse) will be measured at 
screening for all subjects. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 49


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 49 of 120 
During in-clinic treatment (Days 1-3 mandatory; Days 4-7 if subject receives all lofexidine 
doses in the clinic), resting (sitting [or recumbent if necessary because of an AE]) and 
standing (if able) systolic and diastolic blood pressure and pulse will be measured within 
30 minutes before every dose and 3.5 hours (±15 minutes) after administration of study 
medication at 8 AM, 1 PM, and 6 PM; oral temperature and respiration before 8 AM dose 
only. 
During outpatient treatment (Days 4-14) resting (sitting [or recumbent if necessary because 
of an AE]) and standing (if able) systolic and diastolic blood pressure and pulse will be 
measured before an in-clinic dose of lofexidine and 3.5 hours (±30 minutes) after dosing on 
Days 4-13 and once before any dose on Day 14.  If the subject cannot stay in the clinic for 
measurement of the 3.5-hour post-dose vital signs required on Days 4-13, they will be given 
a portable digital blood pressure machine for measurement of their vital signs at this required 
time point and the values will be recorded in a subject diary (Appendix 3). 
For the orthostatic vital sign (i.e., blood pressure and pulse) readings, subjects will remain at 
rest for 3 minutes before a vital sign reading, and then stand for 3 minutes before a second 
vital sign reading is taken.  If a subject demonstrates potentially clinically significant vital 
signs (whether pre- or post-dose), as per the pre-defined criteria detailed in Sections 13.2.2 
and 13.2.3, the event should be recorded on the subject’s eCRF as an AE or SAE (see 
Sections 15.5.1, 16.7, and 16.8) and the subject should be followed until medically stabilized 
to the satisfaction of the study physician. 
Additionally, when the subject is experiencing blood pressure- or pulse-related symptoms 
(e.g., lightheaded, dizziness, palpitations), these should be recorded on the subject’s eCRF as 
an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) even if the vital signs values do not meet 
the pre-defined criteria detailed in Sections 13.2.2 and 13.2.3. 
15.5.3 12-Lead Electrocardiograms 
Using the ECG core lab-provided and validated instruments, baseline paper tracing 12-lead 
ECG (in duplicate) will be conducted on one day during the screening period at 8 AM (or as 
close to 8 AM as possible) and at 11:30 AM.  Note that a time delay for the 8 AM ECG will 
not be considered a protocol deviation, but that the second ECG should be taken 3.5 hours 
after the first ECG.  Duplicate 12-lead ECGs will also be conducted before the first dose on 
Day 1 at 8 AM and 3.5 hours (±15 minutes) after dosing; before the subject’s last dose and 
3.5 hours after dosing (or as close to this time as possible); or, if applicable, at 
discontinuation from the study.  ECG intervals and abnormalities will be read centrally by a 
computer and confirmed by an individual accredited to read ECGs at the ECG core lab 
.  A qualified physician on site will evaluate tracings if there is a significant 
abnormality.  The following intervals will be computed: 
 Ventricular Rate 
Number of R waves appearing within a 6-second period, 
multiplied by 10; 
 PR Interval 
Measured from the onset of the P wave to the onset of the 
QRS complex; 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 50


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 50 of 120 
 QRS Complex 
Measured from the beginning of the down stroke of the 
Q wave to the completion of the upstroke of the S wave; 
 QT Interval 
Measured from the beginning of the down stroke of the 
Q wave to the completion of the T wave; 
 QTc (Bazett) 
QT interval corrected for heart rate using Bazett’s formula  
(QT/square root of RR); 
 QTc (Fridericia) 
QT interval corrected for heart rate using Fridericia’s  
formula (QT/cube root of RR) (for safety monitoring/subject 
discontinuation purposes). 
At screening (baseline assessment), a QTcF interval greater 
than 450 msec for males and greater than 470 msec for 
females will exclude the subject from study participation 
(see exclusion criterion #6 in Section 11.2.2).  In such cases, 
2 additional ECGs should be taken at 10- to 15-minute 
intervals.  The QTcF interval on all 3 ECGs should be 
confirmed by the Principal Investigator and if 2 of the 3 
QTcF intervals exceed the gender-specific cut-off, then the 
subject should be judged a screen failure. 
During the treatment phase of the study, when any QTcF 
interval exceeds 495 msec, 2 additional ECGs should be 
taken at 10- to 15-minute intervals.  The QTcF interval on 
all 3 ECGs should be confirmed by the Principal 
Investigator.  If it is determined that 2 of the 3 QTcF 
intervals exceed 500 msec or >25% above screen value, then 
the subject will be discontinued from the study. 
Any time that 2 of the 3 QTcF measurements exceed 
500 msec, contact the Sponsor’s Medical Safety Monitor, 
 
to discuss the subject and the 
AE/SAE determination. 
15.5.4 Clinical Laboratory Evaluations 
15.5.4.1 Standard Laboratory Tests 
Standard clinical laboratory safety evaluations (see Table 3) will be performed for all 
subjects at screening, as needed at the study physician’s discretion throughout the study, and 
at discontinuation from the study.  For this multicenter study, a central laboratory 
 
will be used that is directly accredited by the College of 
American Pathologists (CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed every 2 years.  The 
laboratory will need to provide a copy of current certification and provide the normal values 
for all analytes to determine the upper limit of normal (ULN). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 51


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 51 of 120 
Table 3. Hematology, Chemistry, and Urinalysis Tests 
Hematology (a) 
Chemistry (b) 
Urinalysis 
Hemoglobin 
Cholesterol 
Color 
Hematocrit 
Triglycerides 
Clarity 
Red blood cell (RBC) count 
Sodium 
pH 
MCV 
Potassium 
Specific gravity 
MCH 
Chloride 
Protein 
MCHC 
Carbon dioxide (CO2) 
Glucose 
RDW 
Glucose 
Ketones 
White blood cell (WBC) count 
Creatinine 
Bilirubin 
WBC differential (% and Abs) 
Albumin 
Nitrite 
neutrophils 
Total protein 
Blood 
lymphocytes 
Calcium 
Urobilinogen 
monocytes 
Phosphorus 
WBC 
eosinophils 
Aspartate aminotransferase (AST) 
RBC 
basophils 
Alanine aminotransferase (ALT) 
Epithelial cells 
Prothrombin time (PT) 
Gamma-glutamyl transpeptidase  
Bacteria 
aPTT 
(GGTP) 
Casts 
Platelet Count 
Total bilirubin 
Crystals 
 
Lactate dehydrogenase (LDH) 
Leukocyte esterase 
 
Alkaline phosphatase 
 
 
Blood urea nitrogen (BUN) 
 
 
Thyroid-stimulating hormone (TSH) 
 
 
Free thyroxine (T4) 
 
Abbreviations:  Abs = absolute; aPTT = activated partial thromboplastin time; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; MCHC = mean corpuscular hemoglobin concentration; 
RDW = red blood cell distribution width 
(a) Blood will be collected in anticoagulant containing evacuated venous blood collection tubes 
(e.g., Vacutainer™). 
(b) Blood will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures. 
 
15.5.4.2 Infectious Disease Panel and Syphilis Tests 
The infectious disease panel and syphilis tests will be assayed as a baseline procedure.  Blood 
will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures.  Qualitative 
analysis reporting positive/negative results will be performed for the following analytes: 
Hepatitis B surface antigen (HbsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B core 
antibody (HBcAb), and Hepatitis C virus antibody (anti-HCV).  A PPD skin test for 
tuberculosis and/or a chest x-ray will be performed on all subjects.  If the PPD is positive, a 
chest x-ray is required to assess active tuberculosis.  If the subject reports that s/he has been 
previously positive for the PPD test, the PPD test will not be performed and only a chest 
x-ray will be required.  Syphilis antibody testing will be performed using an automated 
enzyme immunoassay (EIA).  If the EIA is positive, a confirmatory rapid plasma reagin 
(RPR) test will be performed.  If the RPR test is non-reactive, a confirmatory TPPA 
(treponema pallidum particle agglutination assay) test will be performed. 
Any subject with active liver disease, active tuberculosis, or active syphilis (see Table 4 for 
interpretation of the syphilis testing sequence) will not be eligible for study participation and 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 52


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 52 of 120 
the subject will be referred, at subject’s sole expense, for appropriate follow-up and/or 
treatment. 
Table 4. Syphilis Testing Sequence 
 
Test and Result 
 
 
Subject History 
EIA/CIA/MFI 
RPR 
TPPA 
Interpretation 
Eligibility 
Unknown history  
of syphilis 
Non-reactive 
N/A 
N/A 
No serologic 
evidence 
Meets eligibility 
 
Reactive 
Reactive 
N/A 
Untreated or 
recently treated 
syphilis 
Excluded 
 
Reactive 
Non-reactive 
Non-reactive 
Probably false-
positive 
screening test 
Meets eligibility 
 
Reactive 
Non-reactive 
Reactive 
Possible syphilis 
(e.g., early or 
latent) or 
previously 
treated 
May be eligible; 
consult Medical 
Monitor 
Known history  
of syphilis 
Reactive 
Non-reactive 
Reactive 
Past, 
successfully 
treated syphilis 
Probably 
eligible; consult 
Medical Monitor 
Abbreviations:  CIA = chemiluminescence assay; EIA = enzyme immunoassay; MFI = multiplex fluorescent 
immunoassay; N/A = not applicable; RPR = rapid plasma reagin; TPPA = treponema pallidum particle 
agglutination assay  
 
15.5.4.3 Urine Toxicology Screening 
A qualitative urine drug screen (UDS) will be performed at screening and Baseline (Day 1 
before dosing) for all subjects, and every day during in-clinic lofexidine treatment and 
outpatient lofexidine treatment for the following drugs:  amphetamines/methamphetamines, 
methylenedioxymethamphetamine, cocaine, barbiturates, opiates, benzodiazepines, 
cannabinoids, oxycodone, phencyclidine, methadone, and buprenorphine.  The central lab 
will provide standard sets of UDS “dipsticks” for use across all sites. 
15.5.4.4 Pregnancy Test 
A “dip-stick” pregnancy test designed to measure human chorionic gonadotropin will be 
performed on the first day of screening for all subjects, at Baseline (Day 1 before dosing), 
and at discontinuation from the study for all female subjects regardless of their childbearing 
capacity.  The central lab will provide study sites with a supply of pregnancy dipsticks. 
15.5.4.5 Pharmacokinetic Sampling 
A fingerprick blood sample will be collected concurrently with each scheduled ECG during 
the study. 
A fingerprick blood sample will be collected during outpatient treatment when the subject 
reports to the clinic each day (before next scheduled dose) for analysis of plasma lofexidine 
concentration to monitor compliance. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 53


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 53 of 120 
15.5.5 Physical Examination 
A complete physical examination of the oral cavity, head, eyes, ears, nose and throat, 
cardiovascular system, lungs, abdomen (liver/spleen), extremities, skin, neuropsychiatric 
mental status and sensory/motor status, musculoskeletal system, and general appearance will 
be performed at screening for all subjects. 
An update of the Physical Exam is required at Baseline (before dosing on Day 1) and then a 
complete physical examination should be performed 3 to 4 hours after the first dose on 
Day 1, as clinically warranted throughout the study, and at discontinuation from the study. 
Height should be recorded at screening only. 
15.5.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS measures both suicidal ideation and suicidal behavior and will be completed at 
Baseline (before dosing on Day 1), 3.5 hours after the first dose (8 AM) during in-clinic 
lofexidine treatment, once daily before an in-clinic dose of lofexidine during outpatient 
treatment or, if applicable, at discontinuation from the study.  The Baseline version of the 
C-SSRS (Appendix 5) will be used to assess lifetime suicidality on Day 1 (before dosing).  
At all other protocol-specified time points, the C-SSRS – Since Last Visit version 
(Appendix 6) will be used to assess the subject’s suicidality since the last assessment. 
15.6 Other Assessments 
15.6.1 Prior Medications 
All medications taken by the subject for the 30 days before screening and during the 
screening period will be documented on the Prior Medication eCRF.  The reported 
medications will be reviewed and approved by the Principal Investigator/study 
physician/assigned staff for entry into the study. 
All opioids of abuse the subject has used will also be recorded at the screening visit. 
15.6.2 Concomitant Medication Administration 
Concomitant medication administration will be recorded daily.  All concomitant medications 
will be recorded in source and in the subject’s Concomitant Medication eCRF along with 
dose, dates of administration, and reason for use. 
16 REGULATORY AND REPORTING REQUIREMENTS 
16.1 Good Clinical Practices 
This study will be conducted in accordance with the most current version of the International 
Conference on Harmonization (ICH) Guideline for Good Clinical Practices (GCP).  An 
Investigational Site File binder will be provided to all investigational sites with additional 
instruction as well as a place to store regulatory and study documents.  The monitoring of the 
sites participating in the trial (either remote or on site) will be executed according to GCP 
guidelines and with a focused data review approach (Risk Based Monitoring [RBM]).  
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 54


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 54 of 120 
Monitors will examine subjects’ study files including source documents in both the clinic 
files and subjects’ official medical records, and will also review regulatory/essential 
documents such as correspondence with the IRB and the Sponsor (USWM).  Areas of 
particular concern will be subject informed consent issues, protocol adherence, safety 
monitoring, IRB reviews and approvals, safety reports/regulatory forms, subject records, 
study drug accountability, and principal investigator supervision and involvement in the trial.  
Reports will be prepared following each visit and forwarded to the Sponsor’s Clinical Project 
Manager.  Monitors will also prepare follow-up letters detailing their findings and any items 
requiring further resolution or attention by the site.  Follow-up letters will be provided to the 
Principal Investigator, site coordinator, and Sponsor’s Clinical Project Manager. 
16.2 FDA Forms 1572 and Financial Disclosure 
The Principal Investigator will sign a Statement of Investigator (FDA Form 1572) before 
initiating this study.  The names of any sub-investigators must appear on this form. 
The Principal Investigator and sub-investigators will also sign Financial Disclosure forms 
before initiating this study. 
16.3 Institutional Review Board Approval 
Before initiating the study, the Principal Investigator will obtain written IRB approval to 
conduct the study.  Study medication will not be shipped until IRB approval is obtained.  
Should changes to the study protocol become necessary, protocol amendments (provided by 
the Sponsor) will be submitted in writing to the central IRB and the Principal Investigator’s 
IRB for IRB approval before implementation.  In addition, IRBs will approve all advertising 
materials used for subject recruitment and any educational materials given to the subject.  
Annual reports and progress reports will be submitted to the IRB annually or at a frequency 
requested by the IRB. 
The IRB must be a properly constituted board or committee operating in accordance with 
GCP Title 21 Part 56 of the US CFR relating to IRBs and the ICH Guideline for GCP (E6). 
16.4 Informed Consent/HIPAA Authorization 
Properly executed written informed consent, in compliance with 21 CFR 50 and ICH 
guidelines, shall be obtained from each subject before entering the subject into the trial.  
Attention is directed to the basic elements that are required in the informed consent under 
US Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]).  Additional 
elements of informed consent, if appropriate, must be included in the informed consent 
document (21 CFR 50.25[b]).  A standard Informed Consent document will be approved by a 
central IRB.  Any study site that requires a site-specific Informed Consent document must 
have the document approved by the Sponsor before submission to the site’s IRB. The final 
IRB-approved document must be provided to the Sponsor for regulatory purposes. 
All potential subjects for the study will be given a current copy of the Informed Consent 
Form to read.  The Principal Investigator, sub-investigators, or study physician at each site 
will explain all aspects of the study in lay language and answer all of the subject’s questions 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 55


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 55 of 120 
regarding the study.  If the subject desires to participate in the study, s/he will be asked to 
sign the Informed Consent.  No subject will undergo any study procedures before signing the 
Informed Consent form, which should be signed before screening.  A signed copy will be 
given to the subject and a signed original shall be maintained in the subject’s clinical file as 
well as the Regulatory Binder at each study site.  Subjects who refuse to participate or who 
withdraw from the study will be treated without prejudice. 
Each subject must also sign a HIPAA (US Health Insurance Portability and Accountability 
Act) form before his/her participation in the study.  A signed copy must be provided to the 
subject and a signed original shall be maintained in the subject’s clinical file.  
16.5 Drug Accountability 
All study drug required for completion of this study will be provided by the Sponsor 
(USWM).  Upon receipt, the investigator/pharmacist is responsible for taking inventory of 
the investigational agents.  A record of this inventory must be kept and usage must be 
documented.  Any unused or expired investigational agent shall be returned to the Sponsor. 
16.6 Outside Monitoring 
16.6.1 Medical Monitor 
The Sponsor’s (USWM) Medical Monitors, 
 and/or 
 
will be responsible for attempting to establish concurrence with the Principal 
Investigator on the severity and seriousness of any AEs and SAEs, the relatedness to the 
study treatments, the expectedness of the event, and for determining if an SAE should be 
reported to the FDA in a 7- or 15-day expedited report or an annual report (Appendix 7).  
The Sponsor’s Medical Monitor will also be responsible for tracking and assessing trends in 
the SAEs reported.  Further, the Medical Monitor is available to consult with the Principal 
Investigators and coordinators on any medical issues related to the study (e.g., admission 
criteria, concomitant medications) and can be reached at 
 
and/or 
 
16.6.2 Clinical Monitors 
All Investigators will allow the Sponsor or its representatives to periodically audit, at 
mutually convenient times during and after the study, eCRFs and corresponding source 
documents as noted in the monitoring plan for each subject.  Using an RBM approach, 
monitoring may also occur remotely.  Monitoring both on site and via an RBM approach will 
provide an opportunity for evaluation of the progress of the study and to inform the Sponsor 
of potential problems. 
The study will be monitored according to an approved monitoring plan.  The monitors will 
assure that defined data outlined in the monitoring plan are accurate and in agreement with 
source documentation; verify that investigational agents are properly stored and accounted 
for; verify that subjects’ consent for study participation has been properly obtained and 
documented; confirm that research subjects entered into the study meet inclusion and 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 56


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 56 of 120 
exclusion criteria; and assure that all essential documentation required by GCP guidelines are 
appropriately filed. 
In lieu of an investigator meeting, USWM will host a web-based initiation meeting with 
study sites providing at a minimum protocol training, GCP training, CRF completion 
training, and a review of monitoring expectations.  For sites that did not participate in study 
USWM-LX1-3003-1, monitors will additionally conduct a site initiation visit before the start 
of the study.  At this visit, the monitor will assure that proper study-related documentation 
exists, assist in training investigators and other site personnel in study procedures and GCP 
guidelines, confirm receipt of study supplies, and assure that acceptable facilities are 
available to conduct the study. 
Periodic monitoring visits by USWM will be scheduled at appropriate intervals.  At the end 
of the study, they will advise on storage of study records and return of unused study agents.  
All sites should anticipate visits by the Sponsor, its representatives, and the FDA. 
16.7 Adverse Event Reporting 
In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the Principal Investigator or sub-
investigators according to the specific instructions detailed in this section of the protocol and 
Appendix 7.  The occurrence of AEs will be assessed starting at the treatment phase of the 
protocol (i.e., with the first dose of study drug).  Any AE that occurs during screening will be 
recorded in the subject’s Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course 
of the clinical trial, whether or not the event is considered related to the investigational agent 
or clinically significant.  For this study, events reported by the subject, as well as clinically 
significant abnormal findings in the opinion of the Principal Investigator on physical 
examination, laboratory evaluation, or C-SSRS (for example, score of 3 or more on the scale) 
will be considered an AE and will be recorded on the AE eCRF.  A new illness, symptom, 
sign or clinically significant clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE.  Opioid withdrawal symptoms experienced by 
subjects during screening will be recorded on the Medical History eCRF and such symptoms 
will be recorded as AEs during the study even if they do not change or worsen.  Stable 
chronic conditions, such as arthritis, which are present before entry into the clinical trial and 
do not worsen are not considered AEs. 
For each daily AE assessment, details will be recorded in the subject’s source document and 
AE eCRF regarding the type of AE and whether serious (SAE) or non-serious, severity of 
each AE, and the relationship to the study agent.  These categories are asking for the 
Principal Investigator or physician designee’s best judgment of the severity and relatedness 
of each AE.  The Principal Investigator or physician designee will also record, based on 
his/her best judgment, whether the AE is secondary to opioid withdrawal.  In general, an AE 
should not be marked as withdrawal related AND related to study medication.  Also, if the 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 57


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 57 of 120 
sign or symptom is evaluated as part of the COWS assessment, it should generally be 
considered as withdrawal related and so marked if it is also reported as an AE. 
A study physician or assigned staff must review the AE eCRF for any events that are 
reported as beginning or as continuing.  All AEs, including clinically significant abnormal 
findings on laboratory evaluations, regardless of severity, will be followed by a study 
physician until satisfactory resolution. 
16.8 Serious Adverse Events (SAEs) 
Each adverse event or reaction will be classified by the Principal Investigator or physician 
designee as serious or non-serious.  Based on the seriousness of the adverse event or reaction, 
appropriate reporting procedures will be followed. 
The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH-E2A March 1995, as implemented by the US FDA, defines a serious adverse event 
(SAE) or serious adverse drug experience as any untoward medical occurrence at any dose 
that: 
 results in death during the period of protocol-defined surveillance; 
 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.) 
 requires inpatient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability or incapacity; or 
 results in a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life–threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, the 
event may jeopardize the subject and might require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
An unexpected event is one that is not described with respect to nature, severity, or frequency 
in the product package insert or Investigator’s Brochure. 
All subjects with SAEs must be followed up for outcome.  If a study subject withdraws from 
the study or if an investigator decides to discontinue the subject from the study because of a 
SAE, the subject must have appropriate follow-up medical monitoring including, if 
necessary, hospitalization. 
Reporting requirements for SAEs are described in detail in Appendix 7.  There can be serious 
consequences including ultimately, criminal and/or civil penalties for sponsors who fail to 
comply with FDA regulations governing the reporting of SAEs to the FDA.  Any SAEs, 
including death due to any cause, which occurs to any subject entered into treatment in this 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 58


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 58 of 120 
study or within 30 days following cessation of the last dose of treatment with the study 
medication, whether or not considered related to the investigational product, must be reported 
within 24 hours, from the time any study staff member is made aware of such, to the Sponsor 
(USWM). 
16.9 Pregnancy 
Although pregnancy is not considered an AE, it is the responsibility of the Principal 
Investigator or his/her designee to report any pregnancy in a subject (spontaneously reported 
to them or discovered during a protocol-defined pregnancy test) that occurs during the study 
or within 30 days of taking study medication.  All subjects who become pregnant must be 
withdrawn from the study and stop taking study medication.  The site must make appropriate 
effort (i.e., monthly calls) to follow the subject until completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of infant) must also be 
reported to the Sponsor.  If the subject cannot be reached after 3 telephone attempts, a 
certified letter should be sent.  Documentation of follow-up will be recorded in the source 
documents. 
17 STATISTICAL APPROACH 
17.1 General Considerations 
Continuous or ordered categorical variables not subject to censoring will be summarized with 
the mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and 
maximum.  Continuous or ordered categorical variables subject to censoring (e.g., time to 
removal from study treatment) will be summarized by the 25th percentile, median, 75th 
percentile derived from Kaplan-Meier estimates of probabilities.  Unordered categorical 
variables will be summarized with counts and percentages.  Descriptive statistics will be 
provided for the study population overall as well as by gender. 
Detailed methodology for the summary and statistical analyses of the data collected is this 
study will be documented in a Statistical Analysis Plan (SAP), which will be prepared and 
finalized before completion of the study. 
17.2 Assessment of Effectiveness 
Effectiveness measures will be summarized for the following subject cohorts: 

All exposed subjects;

Subjects undergoing abrupt and total withdrawal;

Subjects undergoing buprenorphine-assisted withdrawal;

Subjects transitioning to naltrexone maintenance;

Subjects transitioning to buprenorphine maintenance;

Subjects undergoing partial withdrawal to lower dose (e.g., chronic opioid medication
for pain); and

Any other identifiable cohorts not otherwise noted.
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 59


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 59 of 120 
Descriptive statistics will be provided for: 
 Demographics and baseline characteristics; 
 SOWS-Gossop; 
 COWS numerical score; 
 COWS severity category (i.e., mild, moderate, moderately severe, severe); 
 Number/proportion of subjects successfully completing their pre-defined withdrawal 
treatment goal (e.g., planned detoxification/transition) as assessed by the Principal 
Investigator; 
 Distribution of number of days required to complete withdrawal treatment goal by 
category; 
 Concomitant medications; and 
 Evaluation of subject treatment status 30 days after last dose. 
17.3 Assessment of Safety 
Safety summaries will be provided for subjects who received lofexidine; any safety 
information on subjects who provide informed consent but do not receive lofexidine will be 
included in listings. 
Safety measures will be summarized for the following subject cohorts: 
 All exposed subjects; 
 Subjects undergoing abrupt and total withdrawal; 
 Subjects undergoing buprenorphine-assisted withdrawal; 
 Subjects transitioning to naltrexone maintenance;  
 Subjects transitioning to buprenorphine maintenance; 
 Subjects undergoing partial withdrawal to lower dose (e.g., chronic opioid 
medication for pain); and 
 Any other identifiable cohorts not otherwise noted. 
Descriptive statistics will be provided for: 
 AEs; 
 AEs of special interest, including orthostatic hypotension, 
orthostatic bradycardia, and syncope; 
 Vital signs; 
 ECGs;  
 Clinical laboratory tests; and 
 C-SSRS. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 60


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 60 of 120 
18 DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) 
Data management activities, construction and accuracy of the study database, and statistical 
analytical support will be coordinated through USWM. 
18.1 Data Collection 
Data will be collected at the study sites on source documents, which will be entered at the 
site into electronic CRFs (eCRFs).  CRFs are to be completed on an ongoing basis during the 
study within 2 to 3 business days of a visit.  The medical chart and the source documents are 
the source of verification of data.  CRFs should be completed according to the instructions in 
the Investigational Site File binder. 
The Principal Investigator is responsible for maintaining accurate, complete, and up-to-date 
records for each subject.  The Principal Investigator is also responsible for maintaining any 
source documentation related to the study, including any films, lab reports, or ECG tracings. 
Data generated by this study must be available for inspection by representatives of the 
US FDA, the Sponsor (USWM), the Sponsor’s representatives, the central IRB 
 or 
the site’s IRB. 
18.2 Electronic Data Capture 
Data entered by site personnel into the electronic data capture (EDC) system will be 
reviewed by the Sponsor or designee.  If incomplete or inaccurate data are found, a query in 
the EDC system will be generated for response by the clinical site.  Sites will promptly 
resolve data inconsistencies and errors.  An audit trail of any corrections or changes to the 
data in the EDC system will be maintained.  Feedback regarding CRF issues will be provided 
to all sites. 
The Principal Investigators agree to routine data audits by the staff of USWM or their 
designee.  USWM monitors will periodically visit each site to assure that data entered in the 
EDC system are in agreement with source documents at the sites per the monitoring plan.   
18.3 Data Analysis 
When the study is completed, all data have been entered into the clinical database, and the 
final database has been checked by Quality Assurance and then locked, statistical analysis of 
the data will be performed by USWM’s statisticians or an independent statistician in 
accordance with the Analytical Plan of this protocol (see Section 17) and detailed in the SAP.  
Periodically, during the investigation, USWM or designee will also prepare summary reports 
of the data so that progress of the study can be monitored. 
18.4 Study Documentation and Records Retention 
Study documentation includes all eCRFs, data correction forms, workbooks, source 
documents (paper or electronic), monitoring logs and appointment schedules, sponsor-
investigator correspondence and regulatory documents (e.g., signed protocol and 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 61


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 61 of 120 
amendments, IRB correspondence and approved consent form and signed informed consent 
forms, Statement of Investigator form, and clinical supplies receipt and distribution records). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study.  Accordingly, source documents include, but are not limited to, laboratory reports, 
ECG tracings, x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound 
photographs, subject progress notes, hospital charts or pharmacy records, and any other 
similar reports or records of any procedure performed in accordance with the protocol.  
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.  Any duplicate of a source document to be retained as a 
part of an eCRF should maintain patient confidentiality per HIPAA. 
Government agency regulations and directives require that the investigator must retain all 
study documentation pertaining to the conduct of a clinical trial.  These documents must be 
kept for a minimum of 2 years after the approval of a new drug application (NDA) and 
finalization of all marketing strategies, or if the NDA is not approved, for 2 years after 
discontinuation of the IND, whichever is the later.  In all instances, sites must get permission 
from USWM before disposition of any study documentation and materials. 
18.5 Confidentiality 
18.5.1 Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom 
of Information Act providing, in part, that proprietary information furnished to clinical 
investigators and IRBs will be kept confidential by the FDA only if maintained in confidence 
by the Principal Investigator and IRB. 
By participating in this protocol, the Principal Investigator affirms to USWM that 
information furnished to the Principal Investigator by USWM will be maintained in 
confidence and such information will be divulged to the IRB/Ethical Review Committee (or 
similar or expert committee), affiliated institution, and employees only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution, and 
employees. 
18.5.2 Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, CRFs (electronic or paper), 
reports, and other records will be coded using subject number and initials.  Only research 
staff and USWM staff or their designee will have access to the records.  Subject information 
will not be released without written permission, except as necessary for monitoring by the 
FDA or USWM.  USWM will file for a Certificate of Confidentiality that will cover all sites 
participating in the study (see Appendix 8). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 62


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 62 of 120 
By participating in this protocol the investigator agrees that within local regulatory 
restrictions and ethical considerations, USWM or any regulatory agency may consult and/or 
copy study documents in order to verify eCRF data. 
Subject confidentiality will be maintained in any publications or presentations that result 
from this study. 
19 DISSEMINATION AND PUBLICATION OF STUDY RESULTS 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages publication of such data in reputable scientific journals and at seminars or 
conferences.  The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study is described in the Clinical Trial 
Agreement between the Sponsor and the institution of the Investigator. 
20 PROTOCOL ADHERENCE AND AMENDMENTS 
The Principal Investigator and each sub-investigator must adhere to the protocol as detailed 
in this document.  Only the Sponsor (USWM) may modify the protocol.  All amendments 
that have an impact on subject risk or the study objectives, or require revision of the 
informed consent document, must receive approval from the central IRB/individual site’s 
IRB before their implementation. 
21 QUALITY CONTROL AND QUALITY ASSURANCE 
Following written standard operating procedures, study monitors will verify that the clinical 
trial is conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  Reports on monitoring activities will 
be submitted to the Sponsor. 
The Sponsor (USWM) will secure agreement from all involved parties to ensure direct access 
to all trial-related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by local and regulatory authorities. 
The Sponsor or designee will be the Data Coordinating Center and will implement quality 
control procedures in accordance with GCPs and their internal Standard Operating 
Procedures, beginning with the data entry system and generate data quality control checks 
that will be run on the database.  Any missing data or data anomalies will be communicated 
to the site for clarification and resolution. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 63


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 63 of 120 
22 REFERENCES 
1. 
Substance Abuse and Mental Health Services Administration (SAMHSA), Office of 
Applied Studies (2008).  Results from the 2007 National Survey on Drug Use and 
Health:  National Findings (NSDUH Series H-34, DHHS Publication No.  SMA 
08-4343).  Rockville, MD.  http://oas.samhsa.gov 
2. 
National Institutes of Health.  Fact Sheet-Heroin Addiction.  September 2006.  
Bethesda, MD.  
http://www.nih.gov/about/researchresultsforthepublic/HeroinAddiction.pdf 
3. 
Archibold RC.  In heartland death, traces of heroin’s spread.  New York Times.  
May 30, 2009.  http://www.nytimes.com/2009/05/31/us/31border.html 
4. 
DAWN, Office of Applied Studies.  National Estimates of Drug-Related Emergency 
Department Visits, 2006. 
5. 
Methadone is a schedule II drug.  See 21 C.F.R. § 1308.12(c)(10) (isomethadone); 
§ 1308.12(c)(15) (methadone); and § 1308.12(c)(16) (methadone-intermediate, 
4-cyano-2-dimethylamino-4,4-diphenyl butane).  Buprenorphine is a schedule III drug.  
See 21 C.F.R. § 1308.13(e)(2)(i). 
6. 
Gowing L, Farrell M, Ali R, White JM.  Alpha 2-adrenergic agonists for the 
management of opioid withdrawal.  Cochrane Database Syst Rev 2008, Issue 4. 
7. 
Kahn A, Mumford JP, Rogers GA, Beckford H.  Double-blind study of lofexidine and 
clonidine in the detoxification of opiate addicts in hospital.  Drug Alcohol Depend 
1997;44:57-61. 
8. 
Lin SK, Strang J, Su LW, Tsai CJ, Hu WH.  Double-blind randomized controlled trial 
of lofexidine versus clonidine in the treatment of heroin withdrawal.  Drug Alcohol 
Depend 1997;48:127-133. 
9. 
Carnwath T, Hardman J.  Randomised double-blind comparison of lofexidine and 
clonidine in the out-patient treatment of opiate withdrawal.  Drug Alcohol Depend 
1998;50:251-254. 
10. Gerra G, Zaimovica A, Giusti F, et al.  Lofexidine versus clonidine in rapid opiate 
detoxification.  J Subst Abuse Treatment 2001;21:11-17. 
11. Yu E, Herman BH, Miotto K, et al.  In-patient safety evaluation of lofexidine (alpha-2 
adrenergic agonist) for opiate detoxification.  Drug Alcohol Depend 2001;63: S175. 
12. Yu E, Miotto K, Akerele E, et al.  A phase 3 placebo-controlled, double blind, multi-
site trial of the α2-noradrenergic agonist, lofexidine, for opioid withdrawal.  Drug 
Alcohol Depend 2008;97:158-168. 
13. Gorodetzky CW.  A phase III, randomized, multi-center, double blind, placebo 
controlled study of safety and efficacy of lofexidine for relief of symptoms in subjects 
undergoing inpatient opiate detoxification.  US WorldMeds Report for Protocol 
USWM-LX1-3002, March 14, 2010. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 64


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 64 of 120 
14. Heyman ER.  An open-label, single-dose, pilot study to determine the maximum 
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and 
women.  CardioCore Report 01496KM, April 27, 2010. 
15. Leibowitz MT.  An open-label, single-dose, pilot study to determine the maximum 
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and 
women.  CEDRA Report DCN 01496KM, April 22, 2010. 
16. Gossop M.  The development of a short opiate withdrawal scale (SOWS).  Addict 
Behav 1990;15(5):487-490. 
17. Wesson DR, Ling W.  The clinical opiate withdrawal scale (COWS).  J Psychoactive 
Drugs 2003;35(2):253-9. 
18. Medical Outcomes Systems.  M.I.N.I. International Neuropsychiatric Interview 
(M.I.N.I.), version 6.0 (10/10/10).  https://www.medical-outcomes.com/index/mini/.  
08 March 2013. 
19. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al.  The M.I.N.I. International 
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured 
diagnostic psychiatric interview.  J Clin Psychiatry 1998;59(suppl 20):22-33. 
 
23 PROTOCOL AMENDMENT DETAILS 
Table 5 lists changes made in Amendment No. 01 to the protocol for Study 
USWM-LX1-3003-2. 
Table 6 lists changes made in Amendment No. 02 to the protocol for Study 
USWM-LX1-3003-2. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 65


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 65 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Pages 1-53 
-- 
Pages 1-113 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
Global change to add SOWS-Gossop as an 
assessment, consistent with other lofexidine 
clinical trials. 
Pages 1-53 
-- 
Pages 1-113 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Global change to add C-SSRS as a safety 
assessment, consistent with the current 
guidance to assess suicidality in all clinical 
studies involving central nervous system 
acting drugs. 
Pages 1-53 
Site Investigator 
Pages 1-113 
Principal Site Investigator 
Global change for protocol clarity. 
Pages 1-53 
Attending physician 
Pages 1-113 
Studyattending physician/  staff 
Global change to improve clarity of the 
protocol. 
Pages 1-53 
Case Report Form (CRF) 
Pages 1-113 
Case Report Form (CRF) 
Global change to remove reference to CRF 
as electronic CRFs will be used in the 
study. 
Pages 1-53 
CRO 
Pages 1-113 
CRO 
Global change to remove reference to CRO. 
Pages 1-53 
Number of subjects 200-400 
Pages 1-113 
Number of subjects 250-500200-400 
Global change based on the projected 
number of subjects completing 7 days of 
lofexidine treatment in the companion study 
(USWM-LX1-3003-1) and earlier 
lofexidine clinical programs expected to be 
appropriate for the FDA’s safety database 
requirements. 
Pages 1-53 
10 study sites 
Pages 1-113 
Approximately 2010 study sites 
Global change to allow additional sites to 
account for the potentially higher 
enrollment requirements and target study 
completion timelines 
Pages 1-53 
Structured Clinical Interview for DSM-IV-TR Axis I Disorders 
(SCID) 
Pages 1-113 
Mini International Neuropsychiatric Interview (M.I.N.I.)Structured 
Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) 
Global change for consistency with 
eligibility assessment in the companion 
study, USWM-LX1-3003-1. 
Pages 1-53 
Assessments at clinic visits every other day 
Pages 1-113 
Daily assessments including while inpatient and at daily clinic 
visits during outpatient treatmentClinic visits every other day 
Global change to more fully monitor the 
safety of lofexidine. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 66


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 66 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Pages 1-53 
-- 
Pages 1-113 
Subject Diary 
Global change to allow collection of vital 
signs data in an outpatient setting. 
Pages 1-53 
Pages 1-113 
Minor editorial changes made for 
consistency and to improve clarity of the 
protocol. 
Title Page, Page 1 
-- 
Title Page, Page 1 
Amendment No. 01 Date: 
January 22, 2015 
Administrative change. 
Title Page, Page 1 
Contract Research Organization   TBD 
Title Page, Page 1 
Contract Research Organization    TBD 
Administrative change. 
Header, Pages 2-53 
Protocol No. USWM-LX1-3003-2        February 3, 2012 
Header, Pages 2-113 
Protocol No. . USWM-LX1-3003-2, Amendment No. 01, 
January 22, 2015 
Administrative change. 
-- 
Section 2, Pages 3-5 
This section provides a summary of major changes made to the 
protocol for Study USWM-LX1-3003-2 in this current amendment 
(Amendment No. 01).  Section 23 provides a detailed accounting of 
all changes made in this amendment. 
[See protocol for summary/rationale of major changes.] 
Administrative change. 
Section 2, Page 3, Objective 
The primary objective is to investigate whether variable dose 
lofexidine treatment can be safely and effectively used along with 
usual standard of care in inpatient/outpatient detoxification from 
short-acting opioids in a variety of clinical situations in which the 
subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Section 3, Page 6, Objective 
To primary objective of this study is to continue to investigate the 
safety of lofexidine when administered for at least 7 days at 
clinically relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms 
of acute withdrawal from opioids in a variety of clinical scenarios 
in both in-clinic and outpatient settings.  The effectiveness is also of 
interest.The primary objective is to investigate whether variable 
dose lofexidine treatment can be safely and effectively used along 
with usual standard of care in inpatient/outpatient detoxification 
from short-acting opioids in a variety of clinical situations in which 
the subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 67


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 67 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 3, Study Design 
-- 
Section 3, Page 6, Study Design 
[Section extensively revised. See protocol for revisions.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 2, Page 3, Inclusion Criteria 
1. Be able to verbalize understanding of the consent form, able to 
provide written informed consent, verbalize willingness to 
complete study procedures, and pass the study consent quiz with 
100% accuracy (if necessary, quiz may be administered more 
than one time). 
Section 3, Page 6, Inclusion Criteria 
17. Be able to verbalize understanding of the consent form, able to 
provide written informed consent, and verbalize willingness to 
complete study procedures., and pass the study consent quiz 
with 100% accuracy (if necessary, quiz may be administered 
more than one time). 
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 2, Page 3, Inclusion Criteria 
3. Be seeking treatment for partial or total withdrawal from current 
opioid.  This can include a variety of clinical situations where 
opioid withdrawal illness is likely to occur.  Examples include 
abrupt and total withdrawal, agonist-assisted withdrawal (with 
the exception of methadone), transition to naltrexone or from 
buprenorphine, or decrease in dose (e.g., of chronic opioid 
medication for pain or of buprenorphine for opioid maintenance 
treatment). 
Section 3, Page 7, Inclusion Criteria 
43. Be seeking treatment for partial or total withdrawal from current 
opioid and expected, as determined by the Principal 
Investigator, to benefit from lofexidine treatment for at least 
7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This can 
include a variety of clinical situations where opioid withdrawal 
illness is likely to occur.  Examples include: 
 abrupt and total withdrawal (including from methadone and 
buprenorphine); 
 agonist-assisted total withdrawal (with the exception of 
methadone),; 
 dose reduction of maintenance treatment (e.g., of 
methadone or buprenorphine); and  
 transition from an opioid agonist to naltrexone or from 
buprenorphine maintenance., or decrease in dose (e.g., of 
chronic opioid medication for pain or of buprenorphine for 
opioid maintenance treatment). 
Revised to allow subjects with clinical 
treatment goals for full or partial 
withdrawal from methadone or 
buprenorphine. 
Section 2, Page 3, Inclusion Criteria 
4. Urine toxicology screen positive for opioids (including 
buprenorphine). 
Section 3, Page 7, Inclusion Criteria 
54. Urine toxicology screen positive for opioid(s) relevant to the 
subject’s withdrawal treatment goal (can includeing methadone 
and buprenorphine) at Screening. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 68


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 68 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 4, Inclusion Criteria 
6. Have completed the Clinical Opiate Withdrawal Scale (COWS)
during the Screening period.
Section 3, Page 7, Inclusion Criteria 
6. Have completed the Clinical Opiate Withdrawal Scale (COWS)
during the Screening period. 
Administrative change. 
Section 2, Page 4, Exclusion Criteria 
2. Be currently taking methadone, by self report or positive urine
drug screen.
Section 3, Page 7, Exclusion Criteria 
2. Be currently taking methadone, by self report or positive urine
drug screen. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 2, Page 4, Exclusion Criteria 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine
co administered with methadone is contraindicated.
Section 3, Page 7, Exclusion Criteria 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine
co administered with methadone is contraindicated. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 2, Page 4, Exclusion Criteria 
4.
Have a very serious medical illness not under control2; have
active self-reported acquired immune deficiency syndrome
(AIDS); or have an unstable psychiatric condition (e.g., suicide
risk).  It is the intent of the study to approach as closely as
feasible real-life conditions of treatment of opioid withdrawal.
Section 3, Pages 7-8, Exclusion Criteria 
24. Have a very serious medical illness not under control as
detailed below.

Serious medical illness will be determined at Screening by:
medical history;
physical examination;
12-lead electrocardiogram (duplicate);
clinical laboratory tests, including standard lab tests, an
infectious disease panel for syphilis (excluded if
positive), hepatitis (positive results do not exclude a
prospective subject from participation unless there is an
indication of active liver disease), and hepatitis
(positive results do not exclude a prospective subject
from participation unless there is an indication of active
liver disease); and
tuberculin test (purified protein derivative [PPD])
and/or a chest x-ray (a positive PPD result does not
exclude a prospective subject from participation, but if
diagnostic tests [e.g., chest x-ray] indicate that active
disease is present, the subject will be excluded from
participation).

Have active self-reported acquired immune deficiency
syndrome (AIDS) or self-reported human
immunodeficiency virus (HIV) positive status and taking
Revised for clarity and consistency with 
companion study, USWM-LX1-3003-1. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 69


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 69 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
retroviral medications currently or within the past 4 weeks. 
 Have an unstable psychiatric condition (e.g., suicide risk, 
per Investigator judgment). 
Have a very serious medical illness not under control2; have active 
self-reported acquired immune deficiency syndrome (AIDS); or 
have an unstable psychiatric condition (e.g., suicide risk).  It is the 
intent of the study to approach as closely as feasible real-life 
conditions of treatment of opioid withdrawal. 
Section 2, Page 4, Exclusion Criteria 
6. 
Have participated in an investigational drug study within the 
past 3 months. 
Section 3, Page 8, Exclusion Criteria 
4. Have participated in an investigational drug study within the 
past 30 days3 months. 
Revised for consistency with other 
protocols. 
-- 
Section 3, Page 8, Exclusion Criteria 
5. Have history of lofexidine exposure in a prior clinical trial or 
otherwise. 
Administrative change. 
Section 2, Page 5, Exclusion Criteria 
7. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
 clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTF interval greater than 450 msec for 
males and greater than 470 msec for females); 
 heart rate less than 55 bpm or symptomatic bradycardia; 
 systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
 diastolic blood pressure less than 65 mmHg; 
 blood pressure greater than 155/95 mmHg; and 
 prior history of myocardial infarction. 
Section 3, Page 8, Exclusion Criteria 
6. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
 clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTcF intervals greater than 450 msec for 
males and greater than 470 msec for females); 
 resting pulseheart rate less than 55 bpm or symptomatic 
bradycardia; 
 resting systolic blood pressure less than 95 mmHg or 
symptomatic hypotension; 
 resting diastolic blood pressure less than 65 mmHg; 
 resting blood pressure greater than 155/95 mmHg; and 
 prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the 
above criteria, the value should be confirmed by repeating the 
measurement (twice, if necessary).  If 2 of 3 values meet the above 
criteria, the subject will be excluded from participation. 
Administrative clarification/update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 70


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 70 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 3, Page 9, Exclusion Criteria 
7. 
To avoid drug-drug interactions, subjects requiring the 
following will be excluded: 
 tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and 
 beta-receptor blockers, to avoid the risk of excessive 
bradycardia. 
Added to improve clarity of the protocol. 
Section 2, Page 5 
N 
Total enrollment will depend on subject drop-out rates.  
Approximately 200 to 400 subjects will need to be enrolled 
and enrollment will remain open until a minimum total of 300 
subjects (among this protocol and companion Protocol USWM 
LX1 3003 1) have been treated with lofexidine for a minimum 
of 7 days. 
Section 3, Page 9 
N 
Total enrollment will depend on subject drop-out rates.  
Approximately 250200 to 500400 subjects: will need to be 
enrolled and enrollment will continueremain open until a 
minimum total of 300 subjects (across this protocol and earlier 
lofexidine clinical studies expected to meet FDA safety 
database requirements) (among this protocol and companion 
Protocol USWM LX1 3003 1) have been treated with 
clinically relevant doses of lofexidine for a minimum of 7 
days.  A target of at least 50 subjects each treated for clinical 
scenarios involving methadone or buprenorphine treatment 
will be enrolled (i.e., a total of 50 subjects receiving full or 
partial dose reduction from methadone, methadone-assisted 
withdrawal, and other methadone treatment scenarios and a 
total of 50 subjects receiving full or partial dose reduction 
from buprenorphine, transition to buprenorphine maintenance, 
and other buprenorphine treatment scenarios). 
Administrative update. 
-- 
Section 3, Page 9, Safety Endpoints 
 Occurrence, seriousness, severity, and causality assessment of 
adverse events. 
 Occurrence of adverse events of special interest (i.e., orthostatic 
hypotension, orthostatic bradycardia, syncope). 
 Occurrence of adverse events not related to opioid withdrawal. 
 Descriptive evaluation of vital signs (actual and change from 
baseline) for each time point. 
Added to align with study objectives. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 71


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 71 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
 
 Descriptive evaluation of the three C-SSRS subscales (suicidal 
ideation, suicidal behavior, and intensity of suicidal ideation). 
 Shifts from baseline in physical examination findings will be 
summarized. 
 Descriptive evaluation of clinical laboratory tests of hematology, 
chemistry, and urinalysis (actual and change from baseline). 
 Descriptive evaluation of ECG (actual and change from 
baseline). 
 
Section 2, Page 5, Endpoints 
 Number/proportion of subjects successfully completing planned 
detoxification/transition as assessed by the Site Investigator. 
 Descriptive evaluation of COWS numerical score, COWS 
severity score (i.e., mild, moderate, moderately severe, severe), 
duration of exposure; distribution of number of days required to 
complete detoxification, average daily dose of lofexidine, 
concomitant medications, and linkage to long term care (through 
subject treatment status report at the 30-day post discharge 
follow-up telephone contact). 
Section 3, Page 9, Effectiveness Endpoints 
 Number/proportion of subjects successfully completing their 
pre-defined withdrawal treatment goal (i.e., planned 
detoxification/transition) as assessed by the Principal Site 
Investigator. 
 Distribution of number of days required to complete withdrawal 
treatment goal by category. 
 Descriptive evaluation of SOWS-Gossop. 
 Descriptive evaluation of COWS numerical score and COWS 
severity score (i.e., mild, moderate, moderately severe, severe) 
 Concomitant medication analysis. 
 duration of exposure; distribution of number of days required to 
complete treatment goal by categorydetoxification, average daily 
dose of lofexidine, concomitant medications, and linkage to long 
term care (throughEvaluation of subject treatment status report 
at the 30 days after last dose.post discharge follow-up telephone 
contact). 
Revised to align with study objectives and 
improve clarity of the protocol. 
Section 2, Page 5, Duration 
21 days (maximum duration per subject, including screening) 
Section 3, Page 10, Duration 
2321 days (maximum duration per subject, including screening) 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 72


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 72 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 5, Visits 
All subjects will undergo screening up to 7 days before study 
admission and will have clinic visits at least every other day for up 
to 14 days. 
Section 3, Page 10, Visits 
All subjects will undergo screening up to 97 days before study 
admission and will have clinic visits at least every other day for up 
to 14 days. 
Days 1-3 
 In-clinic setting:  Subjects may be admitted to clinic on Day -1 
Days 4-7 
 In-clinic setting OR daily visits for 4 days if outpatient 
Days 8-14 
 Daily outpatient visits for up 7 days 
Day30 
 Telephone follow-up contact 
Revised to require mandatory inpatient 
treatment for 3 days to allow more frequent 
safety monitoring during anticipated peak 
withdrawal and initiation of lofexidine 
therapy.  Also, option for inpatient/ 
outpatient treatment on Days 4-7 enables 
assessment, as clinically appropriate at the 
discretion of the Investigator, in a more 
flexible, real-world setting. 
Section 2, Page 5, Effectiveness Assessments 
Section 3, Pages 10-11, Safety Assessments 
[Section extensively revised.  See protocol for revisions.] 
Revised for consistency with study design 
changes. 
Section 2, Page 6, Safety Assessments 
Section 3, Page 11, Effectiveness Assessments 
[Section extensively revised.  See protocol for revisions.] 
Revised to align with study objectives and 
improve clarity of the protocol. 
Section 3, Pages 7-10 
Table of Contents, Appendices 
-- 
Section 4, Pages 12-15 
TOC updated to add the following appendices: 
Appendix 1 Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop) 
Appendix 2 Clinical Opiate Withdrawal Scale (COWS) 
Appendix 3 Subject Diary 
Appendix 4 Short-term Withdrawal Treatment Goal 
Appendix 5 Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline Version 
Appendix 6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
Administrative change. 
Section 4, Pages 11-12 
-- 
Section 5, Pages 16-17 
[Abbreviation list updated.] 
Administrative change. 
Section 5.1, Pages 12-13 
-- 
Section 6.1, Page 18 
[Section extensively revised.  See protocol for revisions.] 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 73


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 73 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 5.3, Page 13, First Paragraph 
USWM has conducted 3 clinical trials (open-label tolerability and 
dose-response study and 2 randomized, double-blind, placebo-
controlled efficacy/safety studies) in support of the use of 
lofexidine in acute withdrawal from short-acting opioids. 
Section 6.3, Page 19, First Paragraph 
USWM has completedconducted 3 clinical trials (open-label 
tolerability and dose-response study and 2 randomized, double-
blind, placebo-controlled efficacy/safety studies) in support of the 
use of lofexidine in acute withdrawal from short-acting opioids.  In 
addition, USWM is currently conducting a randomized, double-
blind, placebo-controlled efficacy/safety study (USWM-LX1-3003-
1) of 2 doses of lofexidine (2.4 and 3.2 mg/day).
Administrative update. 
Section 5.4, Page 14, First Paragraph, 1st & 2nd Sentences 
A total of 2,032 subjects from clinical investigations of lofexidine 
(both USWM and externally sponsored) have been exposed to 
doses ranging from 0.1 mg to 4.0 mg total daily doses in a variety 
of dosing schedules from single doses to four times daily (QID) 
treatment over durations ranging from 1 day to 52 months (in the 
case of one antihypertension study).  In addition, an estimated 
214,000 documented BritLofex™ prescriptions have been sold in 
the UK where the standard dosing regimen prescribed is 2.4 mg 
total daily dose (0.8 mg three times daily or 0.6 mg QID) 
introduced on a dose escalation and maintained typically for 7 to 
10 days.   
Section 6.4, Page 20, First Paragraph, 1st & 2nd Sentences 
A total of 2,0442,032 subjects from clinical investigations of 
lofexidine (both USWM and externally sponsored) have been 
exposed to doses ranging from 0.1 mg to 4.0 mg total daily doses in 
a variety of dosing schedules from single doses to four times daily 
(QID) treatment over durations ranging from 1 day to 52 months (in 
the case of one antihypertension study).In addition, over 266,000 an 
estimated 214,000 documented BritLofex™ prescriptions have 
been sold in the UK (since product launch in 1992) where the 
standard dosing regimen prescribed is 2.4 mg total daily dose 
(0.8 mg three times daily or 0.6 mg QID) introduced on a dose 
escalation and maintained typically for 7 to 10 days.   
Administrative update. 
Section 5.5, Page 15 
-- 
Section 6.5, Page 21 
[Section extensively revised.  See protocol for revisions.] 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
Section 5.6, Page 16 
-- 
Section 6.6, Page 21 
[Section extensively revised.  See protocol for revisions.] 
Revised to add rationale for including 
SOWS-Gossop as an outcome measure. 
Section 6, Page 16 
The primary objective is to investigate whether variable dose 
lofexidine treatment can be safely and effectively used along with 
usual standard of care in inpatient/outpatient detoxification from 
short-acting opioids in a variety of clinical situations in which the 
subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Section 7, Page 22 
The primary objective is to continue to investigate the safety of 
lofexidine when administered for at least 7 days at clinically 
relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms of acute 
withdrawal from opioids in a variety of clinical scenarios in both in-
clinic and outpatient settings.  The effectiveness of lofexidine is 
also of interest.The primary objective is to investigate whether 
variable dose lofexidine treatment can be safely and effectively 
used along with usual standard of care in inpatient/outpatient 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 74


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 74 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
detoxification from short-acting opioids in a variety of clinical 
situations in which the subject is experiencing opioid withdrawal, 
excluding only co-administration of methadone. 
Section 9.1, Pages 16-17 
-- 
Section 10.1, Pages 22-23 
[Section extensively revised.  See protocol for revisions.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 9.2, Page 17 
The total enrollment in this study will depend on subject drop-out 
rates in this protocol and in companion study, Protocol USWM-
LX1-3003-1.  It is estimated that approximately 200 to 400 subjects 
will be enrolled in this open-label study in order to accrue a 
sufficiently large safety database for evaluation.  Enrollment will 
remain open until a minimum of 300 subjects (among this protocol 
and companion Protocol USWM-LX1-3003-1) complete a 
minimum of 7 days of treatment with lofexidine. 
Section 10.2, Page 23 
The total enrollment in this study will depend on subject drop-out 
rates in this protocol.  Enrollment will continue until a minimum 
total of 300 subjects (across this protocol and earlier lofexidine 
clinical studies expected to meet FDA safety database 
requirements) have been treated with clinically relevant doses of 
lofexidine for a minimum of 7 days. and in companion study, 
Protocol USWM-LX1-3003-1.  It is estimated that approximately 
250200 to 500400 subjects will be enrolled in this open-label study 
in order to accrue a sufficiently large safety database for 
evaluation.Enrollment will remain open until a minimum of 300 
subjects (among this protocol and companion Protocol USWM-
LX1-3003-1) complete a minimum of 7 days of treatment with 
lofexidine. 
Administrative update. 
Section 9.3, Page 17 
This study will be initiated after completion of the companion 
study, USWM-LX1-3003-1.  The maximum duration of 
participation for each subject in USWM-LX1-3003-2 will be 
21 days, including the Screening period, which can last up to 
7 days, followed by up to 14 days of flexible dose treatment with 
lofexidine.  
The study will be terminated when the database is judged to be 
sufficient, i.e., a minimum of 300 subjects, among this protocol and 
companion Protocol USWM-LX1-3003-1, completing at least 
7 days of treatment with lofexidine.  Enrollment is anticipated to 
take 5 to 10 months to achieve, with the total clinical duration of 
Section 10.3, Page 23 
This study will be initiated after completion of the companion 
study, USWM-LX1-3003-1.  The maximum duration of 
participation for each subject in USWM-LX1-3003-2 will be 
2321 days, including the Screening period, which can last up to 
97 days, followed by up to 14 days of flexible dose treatment 
with lofexidine.  
The study will be terminated when the database is judged to be 
sufficient, i.e., a minimum of 300 subjects (across this protocol and 
earlier lofexidine clinical studies expected to meet FDA safety 
database requirements) have been treated with clinically relevant 
doses of lofexidine for a minimum of 7 days.among this protocol 
Revised for consistency with study design 
changes and to improve clarity of the 
protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 75


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 75 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
USWM-LX1-3003-2 anticipated to be 8 to 12 months. 
and companion Protocol USWM-LX1-3003-1, completing at least 
7 days of treatment with lofexidine.  Enrollment is anticipated to 
take 45 to 10 months to achieve, with the total clinical duration of 
USWM-LX1-3003-2 anticipated to be 8 to 12 months. 
-- 
Section 10.4, Pages 23-24 
[Section added.  See protocol.] 
Added to improve clarity of the protocol. 
Section 10.1, Page 17, First Paragraph, First 3 Sentences 
Any opioid-dependent subject about to undergo complete or partial 
withdrawal from short-acting opioids or on buprenorphine 
maintenance treatment will be eligible for the study.  Entry into this 
study is open to both men and women and to all racial and ethnic 
subgroups.  An attempt will be made to include at least 25% female 
subjects and a mix of ethnicities reflecting the distribution in the 
local geographic regions of the study sites.  
Section 11.1, Page 24, First Paragraph, First 3 Sentences 
Any opioid-dependent subject about to undergo complete or partial 
opioid withdrawal and could benefit for a minimum of a 7-day 
treatment with lofexidine from short-acting opioids or on 
buprenorphine maintenance treatment will be eligible for the study. 
Entry into this study is open to both men and women and to all 
racial and ethnic subgroups.  An attempt will be made to include at 
least 25% female subjects, and a mix of ethnicities reflecting the 
distribution in the local geographic regions of the study sites, and a 
minimum of 50 subjects each on methadone or buprenorphine 
maintenance treatment.   
Revised for consistency with study design 
changes. 
Section 10.2.1, Page 19 
7. Be able to verbalize understanding of the consent form, able to
provide written informed consent, verbalize willingness to
complete study procedures, and pass the study consent quiz with
100% accuracy (if necessary, quiz may be administered more
than one time).
Section 11.2.1, Page 24 
17. Be able to verbalize understanding of the consent form, able to
provide written informed consent, and verbalize willingness to
complete study procedures., and pass the study consent quiz
with 100% accuracy (if necessary, quiz may be administered
more than one time). 
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 76


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 76 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.1, Page 18 
3. Be seeking treatment for partial or total withdrawal from current 
opioid.  This can include a variety of clinical situations where 
opioid withdrawal illness is likely to occur.  Examples include 
abrupt and total withdrawal, agonist-assisted withdrawal (with 
the exception of methadone), transition to naltrexone or from 
buprenorphine, or decrease in dose (e.g., of chronic opioid 
medication for pain or of buprenorphine for opioid maintenance 
treatment). 
Section 11.2.1, Page 25 
43. Be seeking treatment for partial or total withdrawal from 
current opioid and expected, as determined by the Principal 
Investigator, to benefit from lofexidine treatment for at least 
7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This 
can include a variety of clinical situations where opioid 
withdrawal illness is likely to occur.  Examples include: 
 abrupt and total withdrawal (including from methadone and 
buprenorphine); 
 agonist-assisted total withdrawal (with the exception of 
methadone),; 
 dose reduction of maintenance treatment (e.g., of 
methadone or buprenorphine); and  
 transition from an opioid agonist to naltrexone or from 
buprenorphine maintenance., or decrease in dose (e.g., of 
chronic opioid medication for pain or of buprenorphine for 
opioid maintenance treatment). 
Revised to allow subjects with clinical 
treatment goals for full or partial 
withdrawal from methadone or 
buprenorphine. 
Section 10.2.1, Page 18 
4. Urine toxicology screen positive for opioids (including 
buprenorphine). 
Section 11.2.1, Page 25 
54. Urine toxicology screen positive for opioid(s) relevant to the 
subject’s withdrawal treatment goal (can includeing methadone 
and buprenorphine) at Screening. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 10.2.1, Page 18 
6. Have completed the COWS during the Screening period. 
Section 11.2.1, Page 25 
6. Have completed the COWS during the Screening period. 
Administrative change. 
Section 10.2.2, Page 19  
2. Be currently taking methadone, by self report or positive urine 
drug screen. 
Section 11.2.2, Page 25 
2. Be currently taking methadone, by self report or positive urine 
drug screen. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 10.2.2, Page 19 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine 
co administered with methadone is contraindicated. 
Section 11.2.2, Page 25 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine 
co administered with methadone is contraindicated. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 77


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 77 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.2, Page 19 
4.
Have a very serious medical illness not under control2; have
active self-reported acquired immune deficiency syndrome
(AIDS); or have an unstable psychiatric condition (e.g., suicide
risk).  It is the intent of the study to approach as closely as
feasible real-life conditions of treatment of opioid withdrawal.
Section 11.2.2, Pages 25-26 
24. Have a very serious medical illness not under control as
detailed below.

Serious medical illness will be determined at Screening by:
medical history;
physical examination;
12-lead electrocardiogram (duplicate);
clinical laboratory tests, including standard lab tests, an
infectious disease panel for syphilis (excluded if
positive), hepatitis (positive results do not exclude a
prospective subject from participation unless there is an
indication of active liver disease), and hepatitis
(positive results do not exclude a prospective subject
from participation unless there is an indication of active
liver disease); and
tuberculin test (purified protein derivative [PPD])
and/or a chest x-ray (a positive PPD result does not
exclude a prospective subject from participation, but if
diagnostic tests [e.g., chest x-ray] indicate that active
disease is present, the subject will be excluded from
participation).

Have active self-reported acquired immune deficiency
syndrome (AIDS) or self-reported human
immunodeficiency virus (HIV) positive status and taking
retroviral medications currently or within the past 4 weeks.

Have an unstable psychiatric condition (e.g., suicide risk,
per Investigator judgment).
Have a very serious medical illness not under control2; have active 
self-reported acquired immune deficiency syndrome (AIDS); or 
have an unstable psychiatric condition (e.g., suicide risk).  It is 
the intent of the study to approach as closely as feasible real-
life conditions of treatment of opioid withdrawal. 
Revised for clarity and consistency with 
companion study, USWM-LX1-3003-1. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 78


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 78 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.2, Page 19 
6. 
Have participated in an investigational drug study within the 
past 3 months. 
Section 11.2.2, Page 26 
46. Have participated in an investigational drug study within the 
past 30days3 months. 
Revised for consistency with other 
protocols. 
-- 
Section 11.2.2, Page 26 
5. Have history of lofexidine exposure in a prior clinical trial or 
otherwise. 
Administrative change. 
Section 10.2.2, Page 19 
7. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
 clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTF interval greater than 450 msec for 
males and greater than 470 msec for females); 
 heart rate less than 55 bpm or symptomatic bradycardia; 
 systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
 diastolic blood pressure less than 65 mmHg; 
 blood pressure greater than 155/95 mmHg; and 
 prior history of myocardial infarction. 
Section 11.2.2, Page 26 
6. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
 clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTcF intervals greater than 450 msec for 
males and greater than 470 msec for females); 
 resting pulseheart rate less than 55 bpm or symptomatic 
bradycardia; 
 resting systolic blood pressure less than 95 mmHg or 
symptomatic hypotension; 
 resting diastolic blood pressure less than 65 mmHg; 
 resting blood pressure greater than 155/95 mmHg; orand 
 prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the 
above criteria, the value should be confirmed by repeating the 
measurement (twice, if necessary).  If 2 of 3 values meet the above 
criteria, the subject will be excluded from participation. 
Administrative clarification. 
-- 
Section 11.2.2, Page 26 
7. 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
 tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and  
 beta-receptor blockers, to avoid the risk of excessive 
bradycardia. 
Added to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 79


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 79 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.3, Page 20, First Full Paragraph 
Subjects who fail screening for any reason cannot be rescreened for 
study participation at a later time. 
Section 11.3, Page 26, Second Paragraph 
Subjects who fail screening for any reason cannot be rescreened for 
study participation at a later time. 
Administrative change. 
Section 11.2, Page 20, First Paragraph 
Lofexidine will be packaged and distributed through the pharmacy 
coordinating center (TBD).  Lofexidine tablets will be supplied in 
uniquely-identified 80-count bottles, which will be dispensed by the 
study pharmacist as determined clinically appropriate by the Site 
Investigator to the subject in individual prescription bottles.  The 
site will maintain a dispensing log for each bottle and document the 
number of tablets dispensed to each subject along with the number 
of tablets returned, if any, by the subject at each outpatient visit.  
Returned tablets will not be re-dispensed to future subjects. 
Section 12.2, Page 27, First Paragraph 
Lofexidine will be packaged and distributed through the pharmacy 
coordinating center (SharpTBD).  Lofexidine tablets will be 
supplied in uniquely-identified 80-count bottles.  During in-clinic 
treatment, lofexidine doses will be dispensed directly from the 
80-count bottles, whereas for outpatient treatment, doses which will 
be dispensed by the study pharmacist as determined clinically 
appropriate by the Site Principal Investigator or designee to the 
subject in individual prescription bottles.  One to 2 days of 
medication may be dispensed at each daily clinic visit to 
accommodate flexible scheduling (e.g., day and a half worth of 
medication to supply subject from one morning to the next 
afternoon depending on availability for clinic visit).  The site will 
maintain a dispensing log for each bottle and document the number 
of tablets dispensed to each subject along with the number of tablets 
returned, if any, by the subject at each outpatient visit.  Returned 
tablets will not be re-dispensed to future subjects. 
Administrative change/update. 
Section 11.4, Page 21 
Section 12.4, Page 28 
[Section extensively revised.  See protocol for revisions.] 
Administrative change. 
Section 11.5, Page 21 
The investigational agent, lofexidine, will be stored at room 
temperature in a secure location at the dispensing pharmacy. 
Section 12.5, Page 28 
The investigational agent, lofexidine, will be stored at room 
temperature in a secure location at the dispensing pharmacy.The 
investigational agent, lofexidine, will be stored at 68-77°F in a 
secure location at the dispensing pharmacy or site.  Temperature of 
the investigational agent will be maintained at 68-77°F during 
transport.  Temperature of the investigational agent will be 
monitored during storage and transport.  Temperature excursions 
will be reported to the Sponsor and the Sponsor will determine if 
the investigational agent is fit for use. 
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 80


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 80 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 12.6, Page 28, Second Sentence 
During outpatient treatment (Days 4-14), subjects are to record 
doses taken in his/her subject diary. 
Added to improve clarity of the protocol. 
Section 11.8, Pages 21-22 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
 
tricyclic antidepressants – may reduce the efficacy of 
imidazoline derivatives; 
 
alcohol, sedatives, and anesthetics – may interact with 
lofexidine and enhance its central sedative effects; and 
 
beta-receptor blockers – the combination of lofexidine and 
beta-receptor blockers should be used with caution to avoid the 
risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug 
therapy and appropriate caution is warranted in subjects on such 
therapy.  The Principal Investigator may need to lower the subject’s 
antihypertensive dose during the study. 
Section 12.8, Page 29 
Clonidine is specifically prohibited in this study. 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
 
tricyclic antidepressants – may reduce the efficacy of 
imidazoline derivatives; and 
 
alcohol, sedatives, and anesthetics – may interact with 
lofexidine and enhance its central sedative effects; and 
 
beta-receptor blockers – the combination of lofexidine and 
beta-receptor blockers should be used with caution to avoid the 
risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug 
therapy and appropriate caution is warranted in subjects on such 
therapy.  The Principal Investigator may need to lower the subject’s 
antihypertensive dose during the study. 
Lofexidine should generally not be administered concurrently with 
alcohol, sedatives, and anesthetics as these may interact with 
lofexidine and enhance its central sedative effects. 
Revised to improve clarity of the protocol. 
Section 12.2.1, Page 22 
Section 13.2.1, Pages 29-30 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require in-clinic 
treatment for 3 days, either in-clinic or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 12.2.2, Page 23 
Section 13.2.2, Pages 30-31 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol. 
Section 12.2.3, Page23 
Section 13.2.3, Pages 31-32 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol. 
Section 12.3, Page 23 
Section 13.3, Pages 32-33 
[Section extensively revised.  See protocol for changes.] 
Revised for consistency with study design 
changes. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 81


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 81 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 13.4, Page 33 
Section 13.4 Nicotine Replacement Therapy 
[Section added.  See protocol.] 
Added per study design change requiring 
in-clinic treatment for at least 3 days. 
Section 13.1, Page 24, First Paragraph, First Sentence 
Interested subjects, who respond to recruitment materials, will be 
scheduled to meet with a qualified investigative staff member and 
receive an explanation of the study purpose and requirements in lay 
language.   
Section 14.1, Page 33, First Paragraph, First Sentence 
Interested subjects, who respond to recruitment materials and are 
available to stay for the mandatory 3-day in-clinic treatment part of 
the study and available for participation in either an in-clinic or 
outpatient setting for 4 additional days (total commitment of 
7 days), will be scheduled to meet with a qualified investigative 
staff member and receive an explanation of the study purpose and 
requirements in lay language.   
Revised based on study design change 
requiring in-clinic treatment for at least 
3 days. 
Section 13.1, Page 24, Second Paragraph, First Sentence 
If still interested after receiving an explanation of the study, 
subjects will be given an opportunity to review, inquire about, and 
sign the study informed consent form (see Section 15.4).   
Section 14.1, Page 33, Second Paragraph, First Sentence 
If still interested after receiving an explanation of the study, a 
qualified investigative site staff member will review the study 
informed consent form with subjects, and subjects will be given an 
opportunity to review on their own, inquire about, and sign the 
study informed consent form (see Section 16.4).   
Administrative clarification. 
Section 13.1, Page 24, Second Paragraph, 4th & 5th Sentences 
Screening assessments must be completed within a 7-day time 
period, but can be completed as early as screening day 1.  At no 
time during the screening process should individuals be given 
information regarding inclusion or exclusion criteria, with the 
exception that subjects will be informed that they must exhibit signs 
of opioid withdrawal immediately before admission into the study. 
Section 14.1, Page 33, Second Paragraph, 4th & 5th Sentences 
Screening assessments must be completed within a 97-day time 
period, but can be completed as early as the first screening day 1.  
At no time during the screening process should individuals be given 
information regarding inclusion or exclusion criteria, with the 
exception that subjects will be informed that they must exhibit signs 
of opioid withdrawal immediately before admission into the study. 
Administrative clarification. 
Section 13.1, Page 24, Third Paragraph, Second Sentence 
Subjects must complete a consent quiz with 100% accuracy.   
Section 14.1, Page 33, Third Paragraph, Second Sentence 
Subjects must complete a consent quiz with 100% accuracy.   
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 13.1, Page 24, Last Paragraph, Second Sentence 
Subjects who are excluded, or who decline participation, may not 
be rescreened at a later time and will be given referrals to other 
resources in the area. 
Section 14.1, Pages 33-34, Last Paragraph, Second Sentence 
Subjects who are excluded, or who decline participation, may not 
be rescreened at a later time, although at least 30 days must occur 
between screeningsand will be given referrals to other resources in 
the area. 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 82


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 82 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 13.3, Pages 24-25 
Section 14.3, Page 34 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require in-clinic 
treatment for 3 days, either in-clinic or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 13.4, Page 25 
Section 14.4, Page 35 
[Section extensively revised.  See protocol for changes.] 
Administrative update. 
Section 13.5.1, Page 25, Numbered Items 
-- 
Section 14.5.1, Page 35, Numbered Items 
2. Abnormal vital signs or ECG meeting criteria in Section 13.2.3. 
Administrative clarification. 
Section 13.5.1, Page 25, Numbered Items 
4. Evidence of illicit drug use while participating in the study. 
5. Alcohol or other sedative/hypnotic withdrawal signs and 
symptoms developing following enrollment into the study. 
Section 14.5.1, Page 35, Numbered Items 
4. 
Evidence of illicit drug use while participating in the study. 
5. 
Alcohol or other sedative/hypnotic withdrawal signs and 
symptoms developing following enrollment into the study 
(Days 1-3). 
Administrative clarification. 
Section 13.5.2, Page 26, Numbered Items 
1. New onset of clinically significant abnormal ECG (e.g., second 
or third degree heart block or uncontrolled arrhythmia, 
prolonged QTc interval5). 
2. Persistent symptomatic hypotension (e.g., hypotension not 
responding to bed rest). 
4. Persistent hypertension – blood pressure ≥185/110 mmHg 
recorded on 3 separate occasions taken at least 5 minutes apart 
AND within a 1-hour time period.  If all 3 readings are 
≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be terminated. 
Section 14.5.2, Page 36, Numbered Items 
1. New onset of clinically significant abnormal ECG per 
Investigator judgment (e.g., second or third degree heart block or 
uncontrolled arrhythmia, prolonged QTcF interval5). 
2. Persistent symptomatic hypotension (e.g., hypotension not 
responding to bed rest or fluids). 
4. Persistent hypertension – resting blood pressure ≥185/110 
mmHg recorded on 3 separate occasions taken at least 5 minutes 
apart AND within a 1-hour time period.  If all 2 of 3 readings are 
≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. terminated 
Administrative clarification. 
Section 13.5.3, Page 27 
-- 
Section 14.5.3, Page 37, Last Bullet 
 the safety database is judged to be sufficient, i.e., a minimum of 
300 subjects (across this protocol and earlier lofexidine clinical 
studies expected to meet FDA safety database requirements) 
have been treated with clinically relevant doses of lofexidine for 
a minimum of 7 days. 
Administrative update. 
Section 13.6, Page 27 
Section 14.6, Page 37 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol 
and to relax requirements for concomitant 
therapy. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 83


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 83 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14, Page28, Table 1 
Section 15, Pages 39-40, Table 1 
[Table 1 extensively revised.  See protocol for changes.] 
Revised for consistency with study design 
changes. 
Section 14.1, Page 29 
Section 15.1, Pages 41-42 
[Section extensively revised.  See protocol for changes.] 
Administrative update and revised for 
consistency with study design changes. 
-- 
Section 15.2, Page 42 
Section 15.2  Baseline Assessments 
[Section added.  See protocol for changes.] 
Added based on study design changes. 
Section 14.2, Pages 29-30 
Section 15.3, Pages 42-46 
Section extensively revised, including the following subheadings: 
15.3.1  Days 1-3 (Mandatory In-clinic) 
15.3.2  Days 4-7 (In-clinic/Outpatient) 
15.3.3  Days 8-14 (Outpatient Only) 
15.3.4  Study Discontinuation/End of Study 
15.3.5  30-Day Telephone Follow-up Contact 
[See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 14.3.1, Page 30 
At each visit, the Site Investigator will indicate if the subject has 
completed the planned withdrawal or transition and can be 
discharged without further lofexidine treatment. 
Section 15.4.1, Page 46 
15.4.1  Assessment of Completion of Pre-Defined Withdrawal 
Treatment GoalPlanned Detoxification/Transition 
At each visit, The Site Principal Investigator will indicate if the 
subject has completedthe planned withdrawal or transition and can 
be discharged without further lofexidine treatment.his/her pre-
defined withdrawal treatment goal (Appendix 4) on Days 1-7 by 
responding the following question:  “Has the subject’s withdrawal 
treatment goal been reached?”  Note that, per protocol, subjects are 
required to continue on their dose of lofexidine through Day 7 even 
though the subject may have competed his/her withdrawal 
treatment goal before Day 7.  This same assessment will be made at 
each visit during the 7 days of optional outpatient treatment 
(Days 8-14).  This assessment should be completed after the 
SOWS-Gossop and COWS assessments. 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
-- 
Section 15.4.2, Pages 46-47 
15.4.2  Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop 
[Section added.  See protocol.] 
Added as an assessment, consistent with 
other lofexidine clinical trials. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 84


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 84 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.3.2, Page 30, First Sentence 
The COWS will be used to assess the effectiveness of lofexidine in 
alleviation of opioid withdrawal (at least every other day before 
dosing). 
Section 15.4.3, Page 47, First and Second Sentences 
The COWS [17] will be used to assess the effectiveness of 
lofexidine in alleviation of opioid withdrawal(at least every other 
day before dosing), and will be completed after the SOWS-Gossop 
and before the assessment of completion of pre-defined withdrawal 
treatment goal.  It will be completed during screening, at baseline 
(before dosing on Day 1), once daily at 3.5 hours after the first dose 
of study medication during inpatient treatment, and once daily 
before dosing during outpatient treatment. 
Administrative clarification. 
Section 14.4.1, Page 31, First Paragraph 
-- 
Section 15.5.1, Page 47, First Paragraph 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol (i.e., with the first dose of study drug).  Any 
AE that occurs during screening will be recorded in the subject’s 
Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
Administrative clarification. 
Section 14.4.1, Page 31, First Paragraph, First Sentence 
Subjects will be queried about adverse events at least every other 
day by study staff.  If an AE requires medical attention, it should be 
reported to a study physician immediately.   
Section 15.5.1, Page 47, Second Paragraph, First Sentence 
Adverse events will be assessed and recorded around the same time 
each day by study staff during in-clinic lofexidine 
treatment.Subjects will be queried about adverse events at least 
every other day by study staff.. 
Added based on study design change 
requiring in-clinic treatment. 
Section 14.4.1, Page 31, First Paragraph, 5th and 6th Sentences 
After each AE assessment, the physician will record on the AE 
eCRF, according to the procedures described in Section 15.7, the 
type of AE and whether serious (SAE) or non-serious, severity of 
each AE, and the relationship to the study agent.  These categories 
are asking for the physician’s best judgment of the severity and 
relatedness of each AE.  The physician will also record, based on 
his/her best judgment, whether the AE is secondary to opioid 
withdrawal.   
Section 15.5.1, Pages 47-48, Second Paragraph, 6th, 7th & 8th 
Sentences 
ForAfter each daily AE assessment, the physician details will be 
recorded in the subject’s source document and on the AE eCRF, 
according to the procedures described in Section 16.7, the type of 
AE and whether serious (SAE) or non-serious, severity of each AE, 
and the relationship to the study agent.  These categories are asking 
for the Principal Investigator or physician designee’s best judgment 
of the severity and relatedness of each AE.  The Principal 
Investigator or physician designee will also record, based on his/her 
best judgment, whether the AE is secondary to opioid withdrawal 
(see Section 15.5.1.1).  
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 85


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 85 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.1, Page 31, Third Paragraph 
All subjects will be instructed to contact the treating physician if he 
or she feels dizzy (especially on standing from a sitting or lying 
position) and delay additional lofexidine dosing until instructed by 
the physician. 
Section 15.5.1, Page 48, Fourth and Fifth Paragraphs 
During outpatient treatment, subjects will be queried about AEs at 
each daily clinic visit.  All subjects will be instructed to contact the 
studytreating physician or assigned staff if he or she experiences 
any symptoms of hypotension and/or bradycardia (see list in 
Section 13.2.2) feels dizzy (especially on standing from a sitting or 
lying position) and delay additional lofexidine dosing until further 
instructed by the physician. 
All reported AEs will be recorded as described above. 
Revised for consistency with study design 
changes. 
-- 
Section 15.5.1.1, Page 48 
15.5.1.1  Withdrawal-Related Adverse Events 
[Section added.  See protocol.] 
Revised for consistency with companion 
study USWM-LX1-3003-1. 
Section 14.4.2, Pages 31-32 
Section 15.5.2, Pages 48-49 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Also, potentially clinically significant vital 
signs were clarified to improve clarity of the 
protocol. 
Section 14.4.3, Pages 32-33, First Paragraph 
Using ECG core lab-provided and validated instruments, baseline 
paper tracing 12-lead ECG (in duplicate) will be conducted on one 
day during the screening period at 8 AM and 11:30 AM.  Duplicate 
12-lead ECGs will also be conducted before the first daily dose and
3.5 hours after the first daily dose on Days 1 and 14 or, if
applicable, early discharge/termination from the study.  ECG
intervals and abnormalities will be read centrally by a computer and
confirmed by an individual accredited to read ECGs at the ECG
core lab (TBD).  A cardiologist on site will evaluate tracings if
there is significant abnormality.  The following intervals will be
computed:
Section 15.5.3, Page 49, First Paragraph 
Using the ECG core lab-provided and validated instruments, 
baseline paper tracing 12-lead ECG (in duplicate) will be conducted 
on one day during the screening period at 8 AM and 11:30 AM.  
Duplicate 12-lead ECGs will also be conducted before the first 
daily dose on Day 1 at 8 AM and 3.5 hours (± 15 minutes) after 
dosing; before subject’s last dose and after dosing;the first daily 
dose on Days 1 and 14 or, if applicable, early 
discharge/terminationat discontinuation from the study.  ECG 
intervals and abnormalities will be read centrally by a computer and 
confirmed by an individual accredited to read ECGs at the ECG 
core lab 
A qualified physiciancardiologist on 
site will evaluate tracings if there is a significant abnormality.  The 
following intervals will be computed: 
Administrative update and revised to 
improved clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 86


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 86 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.3, Pages 32-33, Bulleted List 
-- 
Section 15.5.3, Page 50, Bulleted List 
 
QTc (Fridericia) 
QT interval corrected for 
heart rate using Fridericia’s formula 
(QT/cube root of RR) (for safety 
monitoring/subject discontinuation 
purposes). 
Added for consistency with companion 
study USWM-LX1-3003-1. 
Section 14.4.3, Page 33, Last Paragraph 
Any time that 2 of the 3 QTc measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor, 
 
 discuss the subject and the 
AE/SAE determination. 
Section 15.5.3, Page 50, Last Paragraph 
Any time that 2 of the 3 QTcF measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor,
 
to discuss the subject and the AE/SAE determination. 
Administrative update to add 
 
as back up Medical Monitor. 
Section 14.4.4.1, Page 33, First Paragraph 
Standard clinical laboratory safety evaluations (see Table 2) will be 
performed for all subjects at screening, as needed at the physician’s 
discretion throughout the study, and on Day 14 or, if applicable, 
early discharge/termination from the study.  For this multicenter 
study, a central laboratory will be identified by the Sponsor which 
is directly accredited by the College of American Pathologists 
(CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed 
every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the normal values for all analytes 
to determine the upper limit of normal (ULN). 
Section 15.5.4.1, Page 50, First Paragraph 
Standard clinical laboratory safety evaluations (see Table 3) will be 
performed for all subjects at screening, as needed at the study 
physician’s discretion throughout the study, and on Day 14 or, if 
applicable, early discharge/termination at discontinuation from the 
study.  For this multicenter study, a central laboratory 
 
will be identified by the Sponsor which used 
that is directly accredited by the College of American Pathologists 
(CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed 
every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the normal values for all analytes 
to determine the upper limit of normal (ULN). 
Administrative clarification/update. 
Section 14.4.4.1, Page 34, Table 2 
Section 15.5.4.1, Page 51, Table 3 
[Table 3 updated.  See protocol.] 
Table 3 was updated for consistency with 
the laboratory tests routinely conducted by 
the central laboratory. 
Section 14.4.4.2, Page 34, First Paragraph, Seventh Sentence 
A rapid plasma reagin (RPR) test for syphilis will be performed.  If 
positive, a confirmatory test (FTA-ABS or MHA-TP) will be 
performed. 
Section 15.5.4.2, Page 51, First Paragraph, Seventh Sentence 
A rapid plasma reagin (RPR) test for sSyphilis antibody testing will 
be performed using an automated enzyme immunoassay (EIA).  If 
the EIA is positive, a confirmatory rapid plasma reagin (RPR) test 
(FTA-ABS or MHA-TP) will be performed.  If the RPR test is non-
reactive, a confirmatory TPPA (treponema pallidum particle 
agglutination assay) will be performed. 
Revised for consistency with tests used by 
the central laboratory. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 87


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 87 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.4.2, Page 34, Second Paragraph 
If either PPD with chest x-ray, chest x-ray, or the confirmatory test 
for RPR is positive, subjects will not be eligible for study 
participation and will be referred, at subject’s sole expense, for 
appropriate follow-up and/or treatment. 
Section 15.5.4.2, Page 52, Second Paragraph 
If either the PPD with chest x-ray, chest x-ray, or the confirmatory 
test for RPR/confirmatory TPPA test is positive, subjects will not 
be eligible for study participation and will be referred, at subject’s 
sole expense, for appropriate follow-up and/or treatment. 
Revised for consistency with tests used by 
the central laboratory. 
Section 14.4.4.3, Page 35 
Qualitative urine drug screening will be performed at screening for 
all subjects and at least every other day during lofexidine treatment. 
Urine will be sent to a central laboratory for qualitative analysis for 
drugs of abuse.  The methodology will detect specific drugs or 
metabolites in the urine. 
Section 15.5.4.3, Page 52 
A qQualitative urine drug screen (UDS)ing will be performed at 
screening and Baseline (Day 1 before dosing) for all subjects, and 
at least every other day during in-clinic lofexidine treatment and 
outpatient treatment for the following drugs:  amphetamines/ 
methamphetamines, cocaine, barbiturates, opiates, benzodiazepines, 
cannabinoids, methadone, and buprenorphine.  The central lab will 
provide standard sets of UDS “dipsticks” for use across all 
sites.Urine will be sent to a central laboratory for qualitative 
analysis for drugs of abuse.  The methodology will detect specific 
drugs or metabolites in the urine. 
Revised to more fully monitor the safety of 
lofexidine.
Section 14.4.4.4, Page 35 
A “dip-stick” pregnancy test designed to measure human chorionic 
gonadotropin will be performed on the first day of screening for all 
subjects and on Day 14 or early completion/early termination for all 
female subjects regardless of their childbearing capacity.  Sites may 
use any FDA-approved urine pregnancy test. 
Section 15.5.4.4, Page 52 
A “dip-stick” pregnancy test designed to measure human chorionic 
gonadotropin will be performed on the first day of screeningfor all 
subjects, at Baseline (Day 1 before dosing), and on Day 14 or early 
completion/early termination at discontinuation from the study for 
all female subjects regardless of their childbearing capacity.  The 
central lab will provide study sites with a supply of pregnancy 
dipsticks.Sites may use any FDA-approved urine pregnancy test. 
Revised for consistency with companion 
study USWM-LX1-3003-1. 
-- 
Section 15.5.4.5, Page 52 
15.5.4.5  Pharmacokinetic Sampling 
A fingerprick blood sample will be collected concurrently with each 
scheduled ECG during the study. 
A fingerprick blood sample will be collected during outpatient 
treatment when the subject reports to the clinic each day (before 
next scheduled dose) for analysis of plasma lofexidine 
concentration to monitor compliance. 
Added to enable QTc-concentration 
analyses as well as to monitor compliance 
during outpatient treatment. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 88


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 88 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.5, Page 35 
A complete physical examination of the oral cavity, head, eyes, 
ears, nose and throat, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, neuropsychiatric mental status and 
sensory/motor status, musculoskeletal system, and general 
appearance should be performed at screening for all subjects, as 
clinically warranted during lofexidine treatment, and on Day 14 or, 
if applicable, early discharge/termination from the study. 
Height should be recorded at screening only. 
Section 15.5.5, Page 52 
A complete physical examination of the oral cavity, head, eyes, 
ears, nose and throat, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, neuropsychiatric mental status and 
sensory/motor status, musculoskeletal system, and general 
appearance willshould be performed at screening for all subjects., 
as clinically warranted during lofexidine treatment, and on Day 14 
or, if applicable, early discharge/termination from the study. 
An update of the Physical Exam is required at Baseline (before 
dosing on Day 1) and then a complete physical examination should 
be performed 3 to 4 hours after the first dose on Day 1, as clinically 
warranted throughout the study, and at discontinuation from the 
study. 
Height should be recorded at screening only. 
Revised for consistency with study design 
changes. 
-- 
Section 15.5.6, Pages 52-53 
15.5.6  Columbia Suicide Severity Rating Scale (C-SSRS) 
[Section added.  See protocol.] 
Added for consistency with the current 
guidance to assess suicidality in all clinical 
studies involving central nervous system 
acting drugs. 
Section 14.5.1, Page 35, Second Paragraph 
-- 
Section 15.6.1, Page 53, Second Paragraph 
All opioids of abuse the subject has used will also be recorded at 
the screening visit. 
Administrative clarification. 
Section 14.5.2, Page 35 
Concomitant medication administration will be recorded at least 
every other day during the study.  All concomitant medications 
should be recorded on the Concomitant Medication eCRF.  The Site 
Investigator should treat the subject according to his/her usual 
standard of care for opioid withdrawal, with the exception that 
methadone is contraindicated for use in subjects taking lofexidine. 
Section 15.6.2, Page 53 
Concomitant medication administration will be recorded dailyat 
least every other day during the study.  All concomitant 
medications willshould be recorded in source and in the subject’s 
Concomitant Medication eCRF along with dose, dates of 
administration, and reason for use.The Site Investigator should treat 
the subject according to his/her usual standard of care for opioid 
withdrawal, with the exception that methadone is contraindicated 
for use in subjects taking lofexidine. 
Revised for consistency with changes made 
in other parts of the protocol. 
Section 15.1, Pages 35-36, Second and Third Sentences 
An Operations Manual will be provided to all investigational sites 
as a study quality assurance tool.  The monitoring of the sites 
participating in the trial will be executed according to GCP 
Section 16.1 Page 53, Second and Third Sentences 
An Investigator Site BinderOperations Manual will be provided to 
all investigational sites with additional instruction as well as a place 
to store regulatory and study documentsas a study quality assurance 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 89


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 89 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
guidelines. 
tool.  The monitoring of the sites participating in the trial (either 
remote or on site) will be executed according to GCP guidelines 
and with a focused data review approach (Risk Based Monitoring 
[RBM]). 
Section 15.4, Page 37, Second Paragraph, Fourth Sentence 
Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.   
Section 16.4, Page 54, Second Paragraph, Fourth Sentence 
Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.   
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 15.6.1, Page 37 
The Sponsor’s (USWM) Medical Monitor will be responsible for 
attempting to establish concurrence with the Site Investigator on the 
severity and seriousness of any AEs and SAEs, the relatedness to 
the study treatments, the expectedness of the event, and for 
determining if the SAE should be reported to the FDA in a 7- or 
15-day expedited report or an annual report (Appendix 1).  The 
Sponsor’s Medical Monitor will also be responsible for tracking 
and assessing trends in the SAEs reported.  Further, the Medical 
Monitor is available to consult with the Site Investigators and 
coordinators on any medical issues related to the study 
(e.g., admission criteria, concomitant medications). 
Section 16.6.1, Page 55 
The Sponsor’s (USWM) Medical Monitors, 
 
 will be responsible for 
attempting to establish concurrence with the Site Principal 
Investigator on the severity and seriousness of any AEs and SAEs, 
the relatedness to the study treatments, the expectedness of the 
event, and for determining if anthe SAE should be reported to the 
FDA in a 7- or 15-day expedited report or an annual report 
(Appendix 61).  The Sponsor’s Medical Monitor will also be 
responsible for tracking and assessing trends in the SAEs reported.  
Further, the Medical Monitor is available to consult with the Site 
Principal Investigators and coordinators on any medical issues 
related to the study (e.g., admission criteria, concomitant 
medications) and can be reached at 
 
and/or 
 
Administrative update to add 
 
as back up Medical Monitor. 
Section 15.6.2, Page 37, First Paragraph 
All Investigators will allow the Sponsor or its representatives to 
periodically audit, at mutually convenient times during and after the 
study, all CRFs (paper and electronic) and corresponding source 
documents for each subject.  These monitoring visits will provide 
an opportunity for evaluation of the progress of the study and to 
inform the Sponsor of potential problems. 
Section 16.6.2, Page 55, First Paragraph 
All Investigators will allow the Sponsor or its representatives to 
periodically audit, at mutually convenient times during and after the 
study, all eCRFs (paper and electronic) and corresponding source 
documents as noted in the monitoring plan for each subject.  Using 
an RBM approach, monitoring may also occur remotely.  These 
monitoring visitsMonitoring both on site and via an RBM approach 
will provide an opportunity for evaluation of the progress of the 
study and to inform the Sponsor of potential problems. 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 90


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
Confidential Information 
Page 90 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 15.6.2, Page 38, Third Paragraph 
Monitors will conduct a site initiation visit before the start of the 
study.  At this visit, the monitor will assure that proper study-
related documentation exists, assist in training investigators and 
other site personnel in study procedures and GCP guidelines, 
confirm receipt of study supplies, and assure that acceptable 
facilities are available to conduct the study. 
Section 16.6.2, Page 55, Third Paragraph 
In lieu of an investigator meeting, USWM will host a web-based 
initiation meeting with study sites providing at a minimum protocol 
training, GCP training, CRF completion training, and a review of 
monitoring expectations.  For sites that did not participate in study 
USWM-LX1-3003-1, mMonitors will additionally conduct a site 
initiation visit before the start of the study.  At this visit, the 
monitor will assure that proper study-related documentation exists, 
assist in training investigators and other site personnel in study 
procedures and GCP guidelines, confirm receipt of study supplies, 
and assure that acceptable facilities are available to conduct the 
study. 
Administrative change. 
Section 15.6.2, Page 38, Fourth Paragraph, First Sentence 
Routine monitoring visits by USWM will be scheduled at 
appropriate intervals but more frequently at the beginning of the 
study.  At these visits, the monitors will verify that study 
procedures are being conducted according to the protocol 
guidelines and review AEs and SAEs. 
Section 16.6.2, Page 55, Fourth Paragraph, First Sentence 
PeriodicRoutine monitoring visits by USWM will be scheduled at 
appropriate intervals.but more frequently at the beginning of the 
study.  At these visits, the monitors will verify that study 
procedures are being conducted according to the protocol 
guidelines and review AEs and SAEs. 
Administrative clarification. 
Section 15.7, Page 38, First Paragraph, Last Sentence 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol. 
Section 16.7, Page 56, First Paragraph, 2nd, 3rd, & 4th Sentences 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol (i.e., with the first dose of study drug).  Any 
AE that occurs during screening will be recorded in the subject’s 
Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
Administrative clarification. 
Section 15.7, Page 38, Second Paragraph 
An AE is defined as any reaction, side effect, or untoward event 
that occurs during the course of the clinical trial, whether or not the 
event is considered related to the investigational agent or clinically 
significant.  For this study, events reported by the subject, as well 
as clinically significant abnormal findings on physical examination 
or laboratory evaluation will be recorded on the AE eCRF.  A new 
illness, symptom, sign or clinically significant clinical laboratory 
abnormality or worsening of a pre-existing condition or 
abnormality is considered an AE.  Stable chronic conditions, such 
Section 16.7, Page 56, Second Paragraph 
An AE is defined as any reaction, side effect, or untoward event 
that occurs during the course of the clinical trial, whether or not the 
event is considered related to the investigational agent or clinically 
significant.  For this study, events reported by the subject, as well 
as clinically significant abnormal findings in the opinion of the 
Principal Investigator on physical examination, or laboratory 
evaluation, or C-SSRS (for example, score of 3 or more on the 
scale) will be considered an AE and will be recorded on the AE 
eCRF.  A new illness, symptom, sign or clinically significant 
Administrative clarification/update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 91


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 91 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
as arthritis, which are present before clinical trial entry and do not 
worsen are not considered AEs. 
clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE.  Opioid withdrawal 
symptoms experienced by subjects during screening will be 
recorded on the Medical History eCRF and such symptoms will be 
recorded as AEs during the study even if they do not change or 
worsen.  Stable chronic conditions, such as arthritis, which are 
present before entry into the clinical trial and do not worsen are not 
considered AEs. 
Section 15.7, Page 38, Third Paragraph, 1st & 2nd Sentences 
After each AE assessment, the physician will record on the AE 
eCRF the type of AE and whether serious (SAE) or non-serious, 
severity of each AE, and the relationship to the study agent.  These 
categories are asking for the physician’s best judgment of the 
severity and relatedness of each AE.   
Section 16.7, Page 56, Third Paragraph, 1st & 2nd Sentences 
ForAfter each daily AE assessment, the physician details will be 
recorded in the subject’s source document and on theAE eCRF 
regarding the type of AE and whether serious (SAE) or non-serious, 
severity of each AE, and the relationship to the study agent.  These 
categories are asking for the Principal Investigator or physician 
designee’s best judgment of the severity and relatedness of 
each AE. 
Administrative clarification. 
Section 15.9, Page 40 
Although pregnancy is not considered an AE, it is the responsibility 
of the Site Investigator or his or her designee to report any 
pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs 
during the study or within 30 days of completing the study 
medication.  All subjects who become pregnant must be withdrawn 
from study medication and must be followed to the 
completion/termination of the pregnancy.  If the pregnancy 
continues to term, the outcome (health of infant) must also be 
reported to the Sponsor. 
Section 16.9, Page 57 
Although pregnancy is not considered an AE, it is the responsibility 
of the PrincipalSite Investigator or his/or her designee to report any 
pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs 
during the study or within 30 days of takingcompleting the study 
medication.  All subjects who become pregnant must be withdrawn 
from the study and stop taking study medication.  and must be 
followed to the completion/ termination of the pregnancy.  The site 
must make appropriate effort (i.e., monthly calls) to follow the 
subject until completion/termination of the pregnancy.  If the 
pregnancy continues to term, the outcome (health of infant) must 
also be reported to the Sponsor. If the subject cannot be reached 
after 3 telephone attempts, a certified letter should be sent.  
Documentation of follow-up will be recorded in the source 
documents. 
Administrative update. 
Section 16.2, Page 40, Fourth Bullet 
 Subjects completing final buprenorphine withdrawal; 
Section 17.2, Page 58, Fourth Bullet 
 Subjects completing final buprenorphine withdrawal; 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 92


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 92 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 16.2, Page 41, Bulleted Items 
Descriptive statistics will be provided for: 
 Demographics and baseline characteristics; 
 COWS numerical score; 
 COWS severity category (i.e., mild, moderate, moderately 
severe, severe); 
 Duration of exposure to lofexidine; 
 Number of subjects successfully completing planned 
detoxification/transition as assessed by the Site Investigator; 
 Distribution of number of days required to complete 
detoxification; 
 Average daily dose of lofexidine; 
 Concomitant medications; 
 Linkage to long-term care (through subject treatment status report 
at the 30-day post discharge follow-up telephone contact); and 
 Compliance in taking lofexidine (based on pill counts). 
Section 17.2, Pages 58-59, Bulleted Items 
Descriptive statistics will be provided for: 
 Demographics and baseline characteristics; 
 SOWS-Gossop; 
 COWS numerical score; 
 COWS severity category (i.e., mild, moderate, moderately 
severe, severe); 
 Duration of exposure to lofexidine; 
 Number/proportion of subjects successfully completing the pre-
defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Site Principal 
Investigator; 
 Distribution of number of days required to complete withdrawal 
treatment goal by categorydetoxification; 
 Average daily dose of lofexidine; 
 Concomitant medications; and 
 Linkage to long-term care (throughEvaluation of subject 
treatment statusreport at the 30 -days after last dose.post 
discharge follow-up telephone contact).; and 
 Compliance in taking lofexidine (based on pill counts). 
Revised for consistency with study design 
changes. 
Section 16.3, Page 41, Bulleted Items 
Safety measures will be summarized for the following subject 
cohorts: 
 All treated subjects; 
 Treated subjects without urinary evidence of illicit drug use; and 
 Treated subjects with urinary evidence of illicit drug use (may be 
further subdivided by type of illicit drug used). 
Descriptive statistics will be provided for: 
 AEs; 
 Vital signs; 
 ECGs; and 
 Clinical laboratory tests. 
Section 17.3, Page 59, Bulleted Items 
Safety measures will be summarized for the following subject 
cohorts: 
 All exposed subjects; 
 Subjects undergoing abrupt and total withdrawal; 
 Subjects undergoing buprenorphine-assisted withdrawal; 
 Subjects transitioning to naltrexone maintenance;  
 Subjects transitioning to buprenorphine maintenance; 
 Subjects undergoing partial withdrawal to lower dose (e.g., 
chronic opioid medication for pain); and 
 Any other identifiable cohorts not otherwise noted. 
 All treated subjects; 
 Treated subjects without urinary evidence of illicit drug use; and 
Revised for consistency with study design 
changes. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 93


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 93 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
 Treated subjects with urinary evidence of illicit drug use (may be 
further subdivided by type of illicit drug used). 
 
Descriptive statistics will be provided for: 
 AEs; 
 AEs of special interest, including orthostatic hypotension, 
orthostatic bradycardia, and syncope; 
 Vital signs; 
 ECGs; and 
 Clinical laboratory tests; and 
 C-SSRS. 
Section 17, Page 42 
Data management activities and statistical analytical support will be 
coordinated through the CRO (TBD).  The CRO will be responsible 
for the construction and accuracy of the study database. 
Section 18, Page 59 
Data management activities, construction and accuracy of the study 
database, and statistical analytical support will be coordinated 
through USWM.the CRO (TBD).  The CRO will be responsible for 
the construction and accuracy of the study database. 
Administrative change. 
Section 17.1, Page 42, First Paragraph 
Data will be collected at the study sites on source documents, which 
will be entered at the site into electronic CRFs (eCRFs), except for 
the COWS assessment, which is a validated paper instrument and 
thus will be collected on paper, scanned, and appended to the 
subject’s eCRF for entry into the database.  The eCRFs and paper 
CRFs will be supplied by the CRO.  CRFs are to be completed on 
an ongoing basis during the study.  The medical chart and the 
source documents are the source of verification of data.  CRFs 
should be completed according to the instructions in the study 
operations manual. 
Section 18.1, Pages 59-60, First Paragraph 
Data will be collected at the study sites on source documents, which 
will be entered at the site into electronic CRFs (eCRFs).,  except for 
the COWS assessment, which is a validated paper instrument and 
thus will be collected on paper, scanned, and appended to the 
subject’s eCRF for entry into the database.The eCRFs and paper 
CRFs will be supplied by the CRO.  CRFs are to be completed on 
an ongoing basis during the study within 2 to 3 business days of a 
visit.  The medical chart and the source documents are the source of 
verification of data.  CRFs should be completed according to the 
instructions in the Investigational Site File binderstudy operations 
manual. 
Administrative change. 
Section 17.1, Page 42, Third Paragraph 
Data generated by this study must be available for inspection by 
representatives of the US FDA, the Sponsor (USWM), the Sponsor 
representatives, and the site’s IRB. 
Section 18.1, Page 60, Third Paragraph 
Data generated by this study must be available for inspection by 
representatives of the US FDA, the Sponsor (USWM), the 
Sponsor’s representatives, the central IRB 
, orand the site’s 
IRB. 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 94


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 94 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 17.2, Page 42 
Section 18.2, Page 60 
18.2 Electronic Data CaptureData Processing, Editing, and 
Control 
[Section extensively revised.  See protocol for changes.] 
Administrative change. 
Section 17.5.2, Page 44, First Paragraph, First and Second 
Sentences 
To maintain subject confidentiality, all laboratory specimens, CRFs 
(electronic or paper), reports, and other records will be coded using 
alpha-numeric identifiers only.  Only research and clinical records 
will be stored in a locked cabinet. 
Section 18.5.2, Page 61, First Paragraph, First and Second 
Sentences 
To maintain subject confidentiality, all laboratory specimens, CRFs 
(electronic or paper), reports, and other records will be coded using 
subject number and initials.alpha-numeric identifiers only.  Only 
research and clinical records will be stored in a locked cabinet. 
Administrative change. 
Section 18, Pages 44-45 
18. PUBLICATIONS OF THE STUDY RESULTS 
It is understood by the Site Investigator that the information 
generated in this study will be used by the Sponsor (USWM) in 
connection with the development of the product and therefore may 
be disclosed to government agencies in various countries.  To allow 
for the use of information derived from the study, it is understood 
that the Site Investigator is obliged to provide the Sponsor with 
complete test results, all study data, and access to all study records. 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages their publication in reputable 
scientific journals and at seminars or conferences.  Because this is a 
multicenter study, the combined results of the study will be 
published before the Investigator submits site-specific results for 
publication.  Any results of medical investigations with the 
Sponsor’s products and/or publication/lecture/manuscripts based 
thereon, shall be exchanged and discussed by the Site Investigator 
and Sponsor representative(s) 60 days before submission for 
publication or presentation.  Due regard shall be given to the 
Sponsor’s legitimate interests, e.g., manuscript authorship, 
obtaining optimal patent protection, coordinating and maintaining 
the proprietary nature of submissions to health authorities, 
coordinating with other ongoing studies in the same field, and 
Section 19, Page 61 
19. DISSEMINATION AND PUBLICATIONS OF THE 
STUDY RESULTS 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages theirpublication of such data in 
reputable scientific journals and at seminars or conferences.  The 
details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study is 
described in the Clinical Trial Agreement between the Sponsor and 
the institution of the Investigator. 
It is understood by the Site Investigator that the information 
generated in this study will be used by the Sponsor (USWM) in 
connection with the development of the product and therefore may 
be disclosed to government agencies in various countries.  To allow 
for the use of information derived from the study, it is understood 
that the Site Investigator is obliged to provide the Sponsor with 
complete test results, all study data, and access to all study records. 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages their publication in reputable 
scientific journals and at seminars or conferences.  Because this is a 
multicenter study, the combined results of the study will be 
published before the Investigator submits site-specific results for 
publication.  Any results of medical investigations with the 
Sponsor’s products and/or publication/lecture/manuscripts based 
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 95


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 95 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
protecting confidential data and information. 
The Sponsor shall be furnished with a copy of any proposed 
publication.  In cases of publications or presentations of material 
arising from multicenter clinical investigations, the Sponsor is to 
serve as coordinator and referee.  Individual investigators who are 
part of a multicenter investigation may not publish or present data 
that are considered common to a multicenter investigation without 
the consent of the other participating investigators and the prior 
review of the Sponsor.  In case of disagreement amongst the 
investigators participating in a multicenter investigation, the 
Sponsor will be the final arbiter.  Sponsor comments shall be given 
without undue delay, and not later than within 60 days.  If they are 
not accepted, the senior author of the manuscript and the Sponsor’s 
representatives shall promptly meet to discuss further and endeavor 
to agree on the final wording and/or disposition of the publication.  
The above procedure also applies to studies that are not completed, 
including those that are prematurely discontinued. 
Results from investigations shall not be made available to any third 
party by the investigating team outside the publication procedure as 
outlined previously.  The Sponsor will not quote from publications 
by investigators in its scientific information and/or promotional 
material without full acknowledgment of the source (i.e., author and 
reference). 
thereon, shall be exchanged and discussed by the Site Investigator 
and Sponsor representative(s) 60 days before submission for 
publication or presentation.  Due regard shall be given to the 
Sponsor’s legitimate interests, e.g., manuscript authorship, 
obtaining optimal patent protection, coordinating and maintaining 
the proprietary nature of submissions to health authorities, 
coordinating with other ongoing studies in the same field, and 
protecting confidential data and information. 
The Sponsor shall be furnished with a copy of any proposed 
publication.  In cases of publications or presentations of material 
arising from multicenter clinical investigations, the Sponsor is to 
serve as coordinator and referee.  Individual investigators who are 
part of a multicenter investigation may not publish or present data 
that are considered common to a multicenter investigation without 
the consent of the other participating investigators and the prior 
review of the Sponsor.  In case of disagreement amongst the 
investigators participating in a multicenter investigation, the 
Sponsor will be the final arbiter.  Sponsor comments shall be given 
without undue delay, and not later than within 60 days.  If they are 
not accepted, the senior author of the manuscript and the Sponsor’s 
representatives shall promptly meet to discuss further and endeavor 
to agree on the final wording and/or disposition of the publication.  
The above procedure also applies to studies that are not completed, 
including those that are prematurely discontinued. 
Results from investigations shall not be made available to any third 
party by the investigating team outside the publication procedure as 
outlined previously.  The Sponsor will not quote from publications 
by investigators in its scientific information and/or promotional 
material without full acknowledgment of the source (i.e., author and 
reference). 
Section 21, Page 46 
-- 
Section 22, Pages 62-63 
[Reference list updated.  See protocol.] 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 96


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 96 of 120 
Table 5. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 23, Pages 64-96 
Section 23 Protocol Amendment Details 
[Section added.  See protocol.] 
Section added to detail the changes made in 
Amendment No. 1. 
-- 
Appendix 1, Page 97 
Appendix 1 Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
-- 
Appendix 2, Page 98 
Appendix 2 Clinical Opiate Withdrawal Scale (COWS) 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
-- 
Appendix 3, Page 99 
Appendix 3 Subject Diary 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
-- 
Appendix 4, Page100 
Appendix 4 Short-term Withdrawal Treatment Goal 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
-- 
Appendix 5, Pages 101-103 
Appendix 5 Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline Version 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
-- 
Appendix 6, Pages 104-106 
Appendix 6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
[Appendix added.  See protocol.] 
Appendix added for protocol completeness. 
 
 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 97


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 97 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Pages 1-113 
Pages 1-120 
Minor editorial changes made for 
consistency and to improve clarity of the 
protocol. 
Title Page, Page 1 
-- 
Title Page, Page 1 
Amendment No. 02 Date: 
May 21, 2015 
Administrative change. 
Header, Pages 2-113 
Protocol No. USWM-LX1-3003-2, Amendment No. 01  
January 22, 2015 
Header, Pages 2-120 
Protocol No. USWM-LX1-3003-2, Amendment No. 0201  
May 21, 2015January 22, 2015 
Administrative change. 
Section 2, Pages 3-5 
-- 
Section 2, Page 3 
[Section updated.  See protocol for revisions.] 
Revised to include a summary of the 
changes made in Amendment No. 02. 
Section 3, Pages 6-7, Exclusion Criteria 
2. Have a very serious medical illness not under control as detailed 
below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (excluded if positive), 
hepatitis (positive results do not exclude a prospective 
subject from participation unless there is an indication of 
active liver disease), and hepatitis (positive results do not 
exclude a prospective subject from participation unless 
there is an indication of active liver disease); and 
Section 3, Pages 7-8, Exclusion Criteria 
2. Have a very serious medical illness not under control as detailed 
below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (subject is excluded if 
positive for active syphilis as per required laboratory 
tests; see also Section 15.5.4.2), hepatitis (positive results 
do not exclude a prospective subject from participation 
unless there is an indication of active liver disease), and 
hepatitis (positive results do not exclude a prospective 
subject from participation unless there is an indication of 
active liver disease); and 
Revised to improve clarity of the protocol. 
Section 3, Page 10, Safety Assessments, Third Bullet 
 Vital signs during outpatient treatment (Days 4-7 optional; Days 
8-14 if subject continues taking lofexidine), including blood 
pressure and pulse at rest (sitting [or recumbent if necessary 
because of an adverse event]) and standing (if able) at least once 
daily before dosing and 3.5 hours after dosing on Days 4-13 and 
once before any dose on Day 14 or, if applicable, at 
discontinuation from the study (note: if subjects cannot stay in 
Section 3, Page 10, Safety Assessments, Third Bullet 
 Vital signs during outpatient treatment (Days 4-7 optional; 
Days 8-14 if subject continues taking lofexidine), including 
blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an adverse event]) and standing (if able) at 
least once daily before an in-clinic dose of lofexidinedosing and 
3.5 hours after dosing on Days 4-13 and once before any dose 
on Day 14 or, if applicable, at discontinuation from the study 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 98


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 98 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
the clinic for measurement of the 3.5-hour post-dose vital signs, 
they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point, with 
values recorded in a subject diary); 
(note: if subjects cannot stay in the clinic for measurement of 
the 3.5-hour post-dose vital signs, they will be given a portable 
digital blood pressure machine for measurement of their vital 
signs at this required time point, with values recorded in a 
subject diary); 
Section 3, Page 10, Safety Assessments, Fourth Bullet 
 
12-lead ECGs (in duplicate) recorded as follows: 
 Day 1 before the first dose at 8 AM and at 3.5 hours after 
dosing; 
 Before subject’s last dose and after dosing or, if applicable, 
at discontinuation from the study; 
Section 3, Page 10, Safety Assessments, Fourth Bullet 
 
12-lead ECGs (in duplicate) recorded as follows: 
 Day 1 before the first dose at 8 AM and at 3.5 hours after 
dosing; 
 Before subject’s last dose and 3.5 hours after dosing (or as 
close to this time as possible) or, if applicable, at 
discontinuation from the study; 
Revised to include a post-dose ECG 
assessment. 
Section 3, Page 11, Safety Assessments, First Bullet 
 
C-SSRS 3.5 hours after the first dose (8 AM) during in-clinic 
treatment, once daily before dosing during outpatient 
treatment, or, if applicable, at discontinuation from the study; 
Section 3, Page 11, Safety Assessments, First Bullet 
 
C-SSRS 3.5 hours after the first dose (8 AM) during in-clinic 
treatment, once daily before an in-clinic dose of 
lofexidinedosing during outpatient treatment, or, if applicable, 
at discontinuation from the study; 
Revised to improve clarity of the protocol. 
Section 3, Page 11, Effectiveness Assessments, First Bullet 
 
SOWS-Gossop 3.5 hours after the first daily dose during in-
clinic treatment; once daily before dosing during outpatient 
treatment; 
Section 3, Page 11, Effectiveness Assessments, First Bullet 
 
SOWS-Gossop 3.5 hours after the first daily dose during in-
clinic treatment; once daily before an in-clinic dose of 
lofexidinedosing during outpatient treatment; 
Revised to improve clarity of the protocol. 
Section 3, Page 11, Effectiveness Assessments, Second Bullet 
 
COWS 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before dosing during outpatient 
treatment; 
Section 3, Page 11, Effectiveness Assessments, First Bullet 
 
COWS 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before an in-clinic dose of 
lofexidinedosing during outpatient treatment; 
Revised to improve clarity of the protocol. 
Section 5, Pages 16-17 
-- 
Section 5, Pages 16-17 
[Abbreviation list updated.] 
Administrative change. 
Section 10.1, Page 23, Last Sentence 
All subjects receiving lofexidine treatment on an outpatient basis 
will be required to return to the clinic daily to undergo specific 
assessments (including qualitative urine drug screening) as listed in 
Table 1 of Section 15. 
Section 10.1, Page 23, Last 2 Sentences 
All subjects receiving lofexidine treatment on an outpatient basis 
will be required to take a dose of lofexidine in the clinic at each 
daily clinic visit, with required clinical return to the clinic daily to 
undergo specific assessments performed before and after dosing 
(including qualitative urine drug screening) as listed in Table 1 of 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 99


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 99 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 15.  Also during outpatient treatment, subjects will be 
required to undergo qualitative urine drug screening at each clinic 
visit. 
Section 10.4, Page 23 
-- 
Section 10.4, Pages 23-24 , First Paragraph, Last Sentence 
Note that should a second or third measurement be required with 
waiting between measurements, the timing of the measurement will 
not be considered a protocol deviation (i.e., outside the protocol-
specified window). 
Revised to improve clarity of the protocol. 
Section 11.2.2, Pages 25-26 
2. Have a very serious medical illness not under control as detailed 
below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (excluded if positive), 
hepatitis (positive results do not exclude a prospective 
subject from participation unless there is an indication of 
active liver disease), and hepatitis (positive results do not 
exclude a prospective subject from participation unless 
there is an indication of active liver disease); and 
Section 11.2.2, Pages 25-26 
2. Have a very serious medical illness not under control as detailed 
below. 
 Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (subject is excluded if 
positive for active syphilis as per required laboratory 
tests; see also Section 15.5.4.2), hepatitis (positive results 
do not exclude a prospective subject from participation 
unless there is an indication of active liver disease), and 
hepatitis (positive results do not exclude a prospective 
subject from participation unless there is an indication of 
active liver disease); and 
Revised to improve clarity of the protocol. 
Section 13.2.1, Page 30, Second Paragraph 
-- 
Section 13.2.1, Page 30, Second Paragraph, Last Sentence 
Note that if the subject is receiving outpatient treatment, he/she is 
required to take a dose of lofexidine in the clinic at each daily clinic 
visit. 
Revised to improve clarity of the protocol. 
Section 13.2.1, Page 30, Third Paragraph, First Sentence 
Optional Outpatient Treatment (Days 8-14) 
Per Principal Investigator judgment, subjects can continue 
lofexidine treatment on an outpatient basis for up to an additional 
7 days, per the dose schedule listed below.   
Section 13.2.1, Page 30, Third Paragraph, First Sentence 
Optional Outpatient Treatment (Days 8-14) 
Per Principal Investigator judgment, subjects can continue 
lofexidine treatment on an outpatient basis for up to an additional 
7 days, per the dose schedule listed below, including taking a dose 
of lofexidine in the clinic at each daily clinic visit.  
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 100


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 100 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.3.1, Page 34, First Paragraph 
-- 
Section 14.3.1, Page 34, First Paragraph, Sixth Sentence 
Note that should a second or third measurement be required with 
waiting between measurements, the timing of the measurement will 
not be considered a protocol deviation (i.e., outside the protocol-
specified window).   
Revised to improve clarity of the protocol. 
Section 14.3.2, Page 34 
Per clinical judgment of the Principal Investigator, subjects can 
continue to receive lofexidine treatment in a clinic setting or can be 
treated outside of the clinic (outpatient) for the remaining 4 days of 
mandatory lofexidine treatment (Days 4-7).  Required clinical 
assessments are detailed in Table 1.  All subjects receiving 
lofexidine treatment on an outpatient basis will be required to return 
to the clinic daily before a scheduled dose for these clinical 
assessments.  Subjects not requiring extended lofexidine treatment 
can be discharged from the study on Day 7 after receipt of at least 
one dose of study drug and after all end-of-study procedures have 
been completed (see Section 15.3.4). 
Section 14.3.2, Page 34 
Per clinical judgment of the Principal Investigator, subjects can 
continue to receive lofexidine treatment in a clinic setting or can be 
treated outside of the clinic (outpatient) for the remaining 4 days of 
mandatory lofexidine treatment (Days 4-7).  Required clinical 
assessments are detailed in Table 1.  All subjects receiving 
lofexidine treatment on an outpatient basis will be required to take a 
dose of lofexidine in the clinic at each daily clinic visit, with 
required clinical assessments performed before and after dosing as 
detailed in Table 1.return to the clinic daily before a scheduled dose 
for these clinical assessments.  Subjects not requiring extended 
lofexidine treatment can be discharged from the study on Day 7 
after receipt of at least one dose of study drug and after all end-of-
study procedures have been completed (see Section 15.3.4). 
Revised to improve clarity of the protocol. 
Section 14.4, Page 35, First Paragraph 
. 
Section 14.4, Page 35, First Paragraph 
 
Revised to account for up to 3 in-office 
screening visits. 
Section 14.4, Page 35, Fourth Paragraph, First Sentence 
 
 
Section 14.4, Page 35, Fourth Paragraph, First Sentence 
 
 
Revised to reflect the increased amount for 
up to 3 in-office screening visits. 
Section 15, Pages 39-40, Table 1 
Section 15, Pages 39-40, Table 1 
[Footnotes revised.  See protocol for revisions.] 
Revised for consistency with changes made 
in other parts of the protocol. 
Section 15.1, Page 41, Fourth Paragraph, First Bullet 
• 
12-lead ECGs (in duplicate) will be done on one day during the 
screening period at 8 AM and 11:30 AM. 
Section 15.1, Page 41, Fourth Paragraph, First Bullet 
• 12-lead ECGs (in duplicate) will be done on one day during the 
screening period at 8 AM (or as close to 8 AM as possible) and 
at 11:30 AM.  Note that a time delay for the 8 AM ECG will not 
be considered a protocol deviation, but that the second ECG 
should be taken 3.5 hours after the first ECG. 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 101


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 101 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 15.3.2, Page 43, First, Second, and Third Bullets 
 Study medication administration QID at 8 AM, 1 PM, 6 PM, 
and 11 PM. 
 SOWS-Gossop 3.5 hours after the first daily dose during in-
clinic treatment; once daily before dosing during outpatient 
treatment. 
 COWS 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before dosing during outpatient treatment. 
Section 15.3.2, Page 43, First, Second, and Third Bullets 
 Study medication administration QID at 8 AM, 1 PM, 6 PM, 
and 11 PM.  Note that if subject is receiving outpatient 
treatment, he/she is required to take a dose of lofexidine in the 
clinic at each daily clinic visit. 
 SOWS-Gossop 3.5 hours after the first daily dose during 
in-clinic treatment; once daily before an in-clinic doseing of 
lofexidine during outpatient treatment. 
 COWS 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before an in-clinic doseing of lofexidine 
during outpatient treatment. 
Revised to improve clarity of the protocol. 
Section 15.3.2, Page 44, Fourth Bullet, First Sentence 
 Vital Signs including blood pressure and pulse at rest (sitting [or 
recumbent if necessary because of an AE]) and standing (if 
able) at least once daily before dosing and 3.5 hours after dosing 
during outpatient treatment.  
Section 15.3.2, Page 44, Fifth Bullet, First Sentence 
 Vital Signs including blood pressure and pulse at rest (sitting [or 
recumbent if necessary because of an AE]) and standing (if 
able) during outpatient treatmentat least once daily before an in-
clinic dose of lofexidine each daydosing and 3.5 hours after 
dosing during outpatient treatment.   
Revised to improve clarity of the protocol. 
Section 15.3.2, Page 44, Ninth Bullet 
 C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours 
after the first dose (8 AM) during in-clinic treatment; once daily 
before dosing during outpatient treatment. 
Section 15.3.2, Page 44, Tenth Bullet 
 C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours 
after the first dose (8 AM) during in-clinic treatment; once daily 
before an in-clinic doseing of lofexidine during outpatient 
treatment. 
Revised to improve clarity of the protocol. 
Section 15.3.3, Page 44, Second Bullet 
 SOWS-Gossop before dosing. 
Section 15.3.3, Page 45, Second Bullet 
 SOWS-Gossop before an in-clinic doseing of lofexidine. 
Revised to improve clarity of the protocol. 
Section 15.3.3, Page 45, First Bullet 
 COWS before dosing. 
Section 15.3.3, Page 45, Third Bullet 
 COWS before an in-clinic doseing of lofexidine. 
Revised to improve clarity of the protocol. 
Section 15.3.3, Page 45, Fifth Bullet, First Sentence 
 Vital Signs, including blood pressure and pulse at rest (sitting 
[or recumbent if necessary because of an AE]) and standing (if 
able) at least once daily before dosing and 3.5 hours after dosing 
on Days 8-13 and once before any dose on Day 14.   
Section 15.3.3, Page 45, Seventh Bullet, First Sentence 
 Vital Signs, including blood pressure and pulse at rest (sitting 
[or recumbent if necessary because of an AE]) and standing (if 
able) at least once daily before an in-clinic dose of lofexidine 
dosing and 3.5 hours after dosing on Days 8-13 and once before 
any dose on Day 14.   
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 102


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 102 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 15.3.3, Page 45, Ninth Bullet 
 C-SSRS (Since Last Visit Version; Appendix 6) before dosing.   
Section 15.3.3, Page 45, Eleventh Bullet 
 C-SSRS (Since Last Visit Version; Appendix 6) before an 
in-clinic doseing of lofexidine. 
Revised to improve clarity of the protocol. 
Section 15.3.4, Page 46, Third Bullet 
 12-lead ECGs (in duplicate) before the subject’s last dose and 
after dosing. 
Section 15.3.4, Page 46, Sixth Bullet 
 
12-lead ECGs (in duplicate) before the subject’s last dose and 
3.5 hours after dosing (or as close to this time as possible). 
Revised to include a post-dose ECG 
assessment. 
Section 15.4.2, Page 46, First Paragraph, First Sentence 
The SOWS-Gossop [16] will be completed by the subject at 
baseline, once daily at 3.5 hours (± 10 minutes) after the first dose 
of study medication during in-clinic treatment and once daily before 
dosing during outpatient treatment.   
Section 15.4.2, Pages 46-47, First Paragraph, First Sentence 
The SOWS-Gossop [16] will be completed by the subject at 
baseline, once daily at 3.5 hours (± 10 minutes) after the first dose 
of study medication during in-clinic treatment and once daily before 
an in-clinic doseing of lofexidine during outpatient treatment.   
Revised to improve clarity of the protocol. 
Section 15.4.3, Page 47, Second Sentence 
It will be completed during screening, at baseline (before dosing on 
Day 1), once daily at 3.5 hours after the first dose of study 
medication during in-clinic treatment, and once daily before dosing 
during outpatient treatment.   
Section 15.4.3, Page 47, Second Sentence 
It will be completed during screening, at baseline (before dosing on 
Day 1), once daily at 3.5 hours after the first dose of study 
medication during in-clinic treatment, and once daily before an 
in-clinic doseing of lofexidine during outpatient treatment.   
Correction and clarification. 
Section 15.5.2, Pages 48-49, Third Paragraph, First Sentence 
During outpatient treatment (Days 4-14) resting (sitting [or 
recumbent if necessary because of an AE]) and standing (if able) 
systolic and diastolic blood pressure and pulse will be measured at 
least once daily before dosing and 3.5 hours (±30 minutes) after 
dosing on Days 4-13 and once before any dose on Day 14.   
Section 15.5.2, Page 49, Second Paragraph, First Sentence 
During outpatient treatment (Days 4-14) resting (sitting [or 
recumbent if necessary because of an AE]) and standing (if able) 
systolic and diastolic blood pressure and pulse will be measured at 
least once daily before an in-clinic dose of lofexidine dosing and 
3.5 hours (±30 minutes) after dosing on Days 4-13 and once before 
any dose on Day 14.   
Revised to improve clarity of the protocol. 
Section 15.5.3, Page 49, First Paragraph 
Using the ECG core lab-provided and validated instruments, 
baseline paper tracing 12-lead ECG (in duplicate) will be conducted 
on one day during the screening period at 8 AM and 11:30 AM.  
Duplicate 12-lead ECGs will also be conducted before the first dose 
on Day 1 at 8 AM and 3.5 hours (±15 minutes) after dosing; before 
the subject’s last dose and after dosing; or, if applicable, at 
discontinuation from the study.  ECG intervals and abnormalities 
will be read centrally by a computer and confirmed by an individual 
accredited to read ECGs at the ECG core lab 
  A 
qualified physician on site will evaluate tracings if there is a 
Section 15.5.3, Page 49, First Paragraph 
Using the ECG core lab-provided and validated instruments, 
baseline paper tracing 12-lead ECG (in duplicate) will be conducted 
on one day during the screening period at 8 AM (or as close to 
8 AM as possible) and at 11:30 AM.  Note that a time delay for the 
8 AM ECG will not be considered a protocol deviation, but that the 
second ECG should be taken 3.5 hours after the first ECG.  
Duplicate 12-lead ECGs will also be conducted before the first dose 
on Day 1 at 8 AM and 3.5 hours (±15 minutes) after dosing; before 
the subject’s last dose and 3.5 hours after dosing (or as close to this 
time as possible); or, if applicable, at discontinuation from the 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 103


Protocol No. USWM-LX1-3003-2, Amendment No. 02 
May 21, 2015 
 
Confidential Information 
 
Page 103 of 120 
Table 6. 
Changes for USWM-LX1-3003-2 Protocol Amendment No. 01 (January 22, 2015)    
USWM-LX1-3003-2, Amendment No. 02 (May 21, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
significant abnormality.  The following intervals will be computed: 
study.  ECG intervals and abnormalities will be read centrally by a 
computer and confirmed by an individual accredited to read ECGs 
at the ECG core lab 
  A qualified physician on site will 
evaluate tracings if there is a significant abnormality.  The 
following intervals will be computed: 
Section 15.5.4.2, Page 52, First Paragraph 
If the PPD with chest x-ray, chest x ray, or RPR/confirmatory 
TPPA test is positive, subjects will not be eligible for study 
participation and will be referred, at subject’s sole expense, for 
appropriate follow-up and/or treatment. 
Section 15.5.4.2, Pages 51-52, Second Paragraph 
Any subject with active liver disease, active tuberculosis, or active 
syphilis (see Table 4 for interpretation of the syphilis testing 
sequence) will not be eligible for study participation and the 
subjectIf the PPD with chest x-ray, chest x ray, or 
RPR/confirmatory TPPA test is positive, subjects will not be 
eligible for study participation and will be referred, at subject’s sole 
expense, for appropriate follow-up and/or treatment. 
Revised to improve clarity of the protocol. 
Section 15.5.4.2, Page 52 
-- 
Section 15.5.4.2, Page 52 
[Table 4 added.  See protocol.] 
Table 4 added to clarify syphilis testing 
results and interpretation for determination 
of subject study eligibility. 
Section 15.5.4.3, Page 52 
A qualitative urine drug screen (UDS) will be performed at 
screening and Baseline (Day 1 before dosing) for all subjects, and 
every day during in-clinic lofexidine treatment and outpatient 
lofexidine treatment for the following drugs:  amphetamines/ 
methamphetamines, cocaine, barbiturates, opiates, benzodiazepines, 
cannabinoids, methadone, and buprenorphine.  The central lab will 
provide standard sets of UDS “dipsticks” for use across all sites. 
Section 15.5.4.3, Page 52 
A qualitative urine drug screen (UDS) will be performed at 
screening and Baseline (Day 1 before dosing) for all subjects, and 
every day during in-clinic lofexidine treatment and outpatient 
lofexidine treatment for the following drugs:  amphetamines/ 
methamphetamines, methylenedioxymethamphetamine, cocaine, 
barbiturates, opiates, benzodiazepines, cannabinoids, oxycodone, 
phencyclidine, methadone, and buprenorphine.  The central lab will 
provide standard sets of UDS “dipsticks” for use across all sites. 
Revised per updated testing procedures at 
the central lab. 
Section 15.5.6, Page 52, First Sentence 
The C-SSRS measures both suicidal ideation and suicidal behavior 
and will be completed at Baseline (before dosing on Day 1), 
3.5 hours after the first dose (8 AM) during in-clinic lofexidine 
treatment, once daily before dosing during outpatient treatment or, 
if applicable, at discontinuation from the study.   
Section 15.5.6, Page 53, First Sentence 
The C-SSRS measures both suicidal ideation and suicidal behavior 
and will be completed at Baseline (before dosing on Day 1), 
3.5 hours after the first dose (8 AM) during in-clinic lofexidine 
treatment, once daily before an in-clinic doseing of lofexidine 
during outpatient treatment or, if applicable, at discontinuation from 
the study.   
Revised to improve clarity of the protocol. 
Section 23, Pages 64-96 
-- 
Section 23, Pages 97-103 
[Table 6 added.  See protocol.] 
Table 6 added to detail the changes made in 
Amendment No. 02. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 104


Confidential Information 
 
Page 1 of 113 
 
 
 
 
CLINICAL STUDY PROTOCOL 
A Phase 3, Open-Label, Safety Study of Lofexidine 
Protocol Number: 
USWM-LX1-3003-2 
Product: 
Lofexidine 
Investigational New Drug (IND) Number: 
IND 47,857 
Development Phase of Study: 
Phase 3 
Medical Monitor: 
 
Sponsor: 
US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 
Louisville, KY  40207 
Protocol Date: 
February 3, 2012 
Amendment No. 01 
January 22, 2015 
Confidentiality Statement:  The information in this document contains trade secrets 
and commercial information that are privileged or confidential and that may not be 
disclosed without the written consent of US WorldMeds, LLC.  Acceptance of this 
document constitutes the agreement of the recipient that this information will not be 
disclosed to others, except to the extent necessary for Institutional Review Board 
procedures and to obtain written informed consent from those persons to whom test 
drug may be administered. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 122


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 2 of 113 
1 SIGNATURE PAGE 
By signing below, US WorldMeds, LLC and the investigator indicate approval of this 
protocol as well as assurance that this study will be conducted according to the procedures 
described in the protocol, Good Clinical Practices, and all applicable regulatory 
requirements. 
 
Protocol Approval: 
 
 
Name (print): 
  
 
 
 
 
 
Investigator Agreement:  I have read the protocol and agree to conduct the study as 
outlined herein. 
 
 
 
Signature: 
 
 
 
Date: 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 123


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 3 of 113 
2 PROTOCOL AMENDMENT SUMMARY 
This section provides a summary of major changes made in this current amendment (No. 01) 
to the protocol for Study USWM-LX1-3003-2.  Section 23 provides a detailed accounting of 
all changes made in this amendment. 
AMENDMENT No. 01: RATIONALE AND SUMMARY OF MAJOR CHANGES 
•
The protocol was revised to allow enrollment of subjects with clinical treatment goals 
for full or partial withdrawal from any opioid (including methadone and 
buprenorphine), which would be expected to elicit opioid abstinence syndrome 
requiring treatment for at least 7 days.  Treatment goals may include abrupt and total 
withdrawal, agonist-assisted total withdrawal, dose reduction of maintenance 
treatment (e.g., methadone, buprenorphine), and transition from an opioid or opioid 
agonist to naltrexone or buprenorphine maintenance.  An attempt will be made to 
include a minimum of 50 subjects each treated for clinical scenarios involving 
methadone or buprenorphine treatment (i.e., a total of 50 subjects receiving full or 
partial dose reduction from methadone, methadone-assisted withdrawal, and other 
methadone treatment scenarios and a total of 50 subjects receiving full or partial dose 
reduction from buprenorphine, transition to buprenorphine maintenance, and other 
buprenorphine treatment scenarios).  The change was introduced to enable the study 
of lofexidine’s utility in any situation in which mitigation of opioid withdrawal 
symptoms would be beneficial to reaching the end treatment goal.  Both 
buprenorphine and methadone clinical scenarios are being evaluated as clinically 
relevant scenarios where lofexidine’s use is likely.  Results of prior interaction studies 
do not suggest a significant safety concern with coadministration of lofexidine and 
both methadone and buprenorphine.  Further evaluation of the safety and clinical 
utility of lofexidine coadministered with methadone or buprenorphine will help 
confirm that a contraindication for use of lofexidine with agonists is unnecessary.
•
The protocol was revised to use the Mini International Neuropsychiatric Interview 
(M.I.N.I.) rather than the Structured Clinical Interview for DSM-IV-TR Axis I 
Disorders (SCID) to establish the appropriate dependence diagnosis on opioids, 
exclude other drug dependency, and determine the absence of major psychiatric 
disorders.  M.I.N.I. is being used for consistency with eligibility assessment in 
companion study, USWM-LX1-3003-1.  Like SCID, the M.I.N.I. is a validated scale 
(Sheehan et al., 1998) and is commonly used in clinical practice and research studies.
•
Number of subjects needed for enrollment was increased from 200 to 400 to
250 to 500 based on the projected number of subjects completing 7 days of lofexidine 
treatment in the companion study (USWM-LX1-3003-1) and FDA’s safety database 
requirements.  Enrollment in USWM-LX1-3003-2 will continue until a minimum of 
300 subjects across the lofexidine studies have received active treatment at clinically 
relevant doses for at least 7 days. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 124


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 4 of 113 
• Number of study sites was increased from 10 to approximately 20 to account for the 
potentially higher enrollment requirements and target study completion timelines. 
• The protocol was revised from flexible dosing to standardized dosing of 7 days of 
lofexidine treatment, starting at 3.2 mg daily (0.8 mg QID), with lowering of the dose 
allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the 
subject’s individual treatment goal and response per clinical judgment of the Principal 
Investigator.  The standard dosing approach is being adopted to limit variability 
across sites and treatment scenarios to ensure interpretability of safety data at 
clinically relevant doses and to evaluate the same doses as used in the controlled 
programs with demonstrated efficacy. 
• The protocol was revised to require 3 days of mandatory in-clinic (inpatient 
housing/clinic facilities) treatment with lofexidine (Days 1-3) and then, per clinical 
judgment of the Principal Investigator, subjects can continue to receive all 4 daily 
doses of lofexidine in the clinic or can be treated as outpatients for the remaining 
4 days of mandatory lofexidine treatment (Days 4-7).  Subjects can continue 
receiving lofexidine on a semi-standardized taper in an outpatient setting as long as 
acute withdrawal symptoms persist at the Principal Investigator’s discretion; 
however, in no event is treatment to exceed an additional 7 days (maximum of 
14 days treatment over entire study).  The required initial 3 days of in-clinic treatment 
was introduced to enable more frequent safety monitoring during anticipated peak 
withdrawal and initiation of lofexidine therapy.  Outpatient treatment for continuation 
of therapy begins at Day 4 to enable assessment, as clinically appropriate at the 
discretion of the Principal Investigator, in a more flexible, real-world setting as 
patients with a variety of treatment goals, as being studied in the current design, may 
not require a longer-term clinic stay and in many situations it may be impractical to 
require inpatient treatment for more than a few days (e.g., work schedules). 
• The protocol was revised to require daily (rather than every other day) assessments, 
including during in-clinic treatment and at daily clinic visits during outpatient 
treatment.  As the primary objective of the study is to assess safety of lofexidine at 
clinically relevant doses, daily evaluations regardless of inpatient or outpatient status 
are appropriate. 
• The Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) was added because 
this scale has been evaluated in nearly all other lofexidine studies in opioid 
withdrawal, serving as the instrument to evaluate efficacy as the primary endpoint in 
the 2 pivotal programs conducted for the drug; and the SOWS-Gossop data will be 
used to evaluate lofexidine’s effectiveness in a variety of open-label clinical scenarios 
studied under the current protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 125


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 5 of 113 
•
Requirements for vital signs were expanded during in-clinic treatment with 
lofexidine, similar to requirements in the companion study (USWM-LX1-3003-1). 
Also a subject diary (Appendix 3) was added if the required post-dose blood 
pressure/pulse measurement cannot be obtained in the clinic.  These changes were 
introduced to ensure the most robust safety data collection possible during the
in-clinic portion of the study and providing a mechanism for additional data 
collection in the outpatient setting, consistent with the primary objective of the study.
•
A fingerprick blood sample concurrently with each scheduled ECG was added to 
enable QTc-concentration analyses.
•
A fingerprick blood sample was added for analysis of plasma lofexidine 
concentration to monitor compliance during outpatient treatment.
•
Columbia Suicide Severity Rating Scale (C-SSRS) was added as a safety assessment, 
consistent with the current guidance to assess suicidality in all clinical studies 
involving central nervous system acting drugs. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 126


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 6 of 113 
3 SYNOPSIS 
Title 
A Phase 3, Open-Label, Safety Study of Lofexidine 
Objective 
The primary objective of the study is to continue to investigate the safety of 
lofexidine when administered for at least 7 days at clinically relevant doses 
(3.2 or 2.4 mg/day) to alleviate symptoms of acute withdrawal from opioids 
in a variety of clinical scenarios in both in-clinic and outpatient settings.  
The effectiveness of lofexidine is also of interest. 
Study Design Multicenter, open-label study in the United States in which subjects will 
receive lofexidine treatment for 7 days, starting at a dose of 3.2 mg daily 
(0.8 mg QID), with lowering of the dose allowed to 2.4 mg daily (0.6 mg 
QID) if required for tolerability based on the subject’s individual treatment 
goal and response per clinical judgment of the Principal Investigator.  Note 
that all subjects will start lofexidine administration (Day 1) on the first day 
of his/her planned opioid agonist dose reduction/discontinuation regardless 
of the clinical situation in which the subject is seeking treatment (see 
Inclusion Criterion No. 3).  All subjects will receive all 4 doses of 
lofexidine in a clinic setting for the first 3 days (Days 1-3) and then, per 
clinical judgment of the Principal Investigator, subjects can continue to 
receive lofexidine doses in a clinic setting or can be treated outside of the 
clinic (outpatient) for the remaining 4 days of mandatory lofexidine 
treatment (Days 4-7).  Per Principal Investigator judgment, subjects can 
continue lofexidine treatment beyond Day 7 on an outpatient basis only for 
up to an additional 7 days (Days 8-14).  Note that lofexidine dosing may be 
stopped at any time during Days 8-14.  No subject will receive lofexidine 
for more than 14 days total.  Subjects will receive a telephone follow-up call 
30 days after their last dose.  
During in-clinic treatment, subjects must take lofexidine within a 1-hour 
window, 30 minutes before or after 8 AM and within a 30-minute window, 
15 minutes before or after 1 PM, 6 PM, and 11 PM.  In the event a subject is 
not dosed within this window as a result of completion of confirmatory vital 
sign assessments (Section 10.4), this will not constitute as a protocol 
deviation.  Source documents must note, however, the reason for dose 
delay.  For subjects receiving outpatient treatment (elective) on Days 4-7 
and those continuing lofexidine treatment in a mandatory outpatient setting 
for up to an additional 7 days (Days 8-14), prescribed dosing will remain on 
the same QID schedule (8 AM, 1 PM, 6 PM, 11 PM).   
Sites 
Approximately 20 (Target:  ≥3-4 subjects/site/month.  Recruitment time: 
4 to 10 months, depending on total enrollment requirements) 
Inclusion 
Criteria 
1. Be able to verbalize understanding of the consent form, able to provide 
written informed consent, and verbalize willingness to complete study 
procedure . 
2. Be male or female at least 18 years of age. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 127


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 7 of 113 
Inclusion 
Criteria 
(continued) 
3. Have current dependence, according to the Mini International 
Neuropsychiatric Interview (M.I.N.I.), on any opioid (including 
methadone and buprenorphine maintenance treatment). 
4. Be seeking treatment for partial or total withdrawal from current opioid 
and expected, as determined by the Principal Investigator, to benefit 
from lofexidine treatment for at least 7 days at clinically relevant doses 
(3.2 or 2.4 mg/day).  This can include a variety of clinical situations 
where opioid withdrawal illness is likely to occur.  Examples include:  
• abrupt and total withdrawal (including from methadone and 
buprenorphine); 
• agonist-assisted total withdrawal; 
• dose reduction of maintenance treatment (e.g., of methadone or 
buprenorphine); and 
• transition from an opioid agonist to naltrexone or buprenorphine 
maintenance. 
5. Urine toxicology screen positive for opioid(s) relevant to the subject’s 
withdrawal treatment goal (can include methadone and buprenorphine) 
at Screening. 
 
6. If female and of childbearing potential, subject must agree to use one of 
the following methods of birth control: 
• oral contraceptives; 
• patch; 
• barrier (diaphragm, sponge or condom) plus spermicidal 
preparations; 
• intrauterine contraceptive system; 
• levonorgestrel implant; 
• medroxyprogesterone acetate contraceptive injection; 
• complete abstinence from sexual intercourse; 
• hormonal vaginal contraceptive ring; or 
surgical sterilization or partner sterile (must have documented proof). 
Exclusion 
Criteria 
1. Be a female subject who is pregnant or lactating. 
2. Have a very serious medical illness not under control as detailed below. 
• Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 128


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 8 of 113 
Exclusion 
Criteria 
(continued) 
 clinical laboratory tests, including standard lab tests, an 
infectious disease panel for syphilis (excluded if positive), 
hepatitis (positive results do not exclude a prospective subject 
from participation unless there is an indication of active liver 
disease), and hepatitis (positive results do not exclude a 
prospective subject from participation unless there is an 
indication of active liver disease); and 
 tuberculin test (purified protein derivative [PPD]) and/or a chest 
x-ray (a positive PPD result does not exclude a prospective 
subject from participation, but if diagnostic tests [e.g., chest 
x-ray] indicate that active disease is present, the subject will be 
excluded from participation). 
 
• Have active self-reported acquired immune deficiency syndrome 
(AIDS) or self-reported human immunodeficiency virus (HIV) 
positive status and taking retroviral medications currently or within 
the past 4 weeks. 
• Have an unstable psychiatric condition (e.g., suicide risk, per 
Investigator judgment). 
3. Current dependence (based on the M.I.N.I.) on any psychoactive 
substance (excluding caffeine, nicotine, and the subject’s current opioid-
dependence agent, which can include methadone or buprenorphine for 
example, in agonist-maintained subjects) that requires detoxification or 
dose reduction as part of the pre-defined individual subject withdrawal 
treatment goal. 
4. Have participated in an investigational drug study within the past 
30 days. 
5. Have history of lofexidine exposure in a prior clinical trial or otherwise. 
 
6. Abnormal cardiovascular exam at Screening, including any of the 
following: 
• clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled arrhythmia, or 
QTcF intervals greater than 450 msec for males and greater than 
470 msec for females); 
• resting pulse less than 55 bpm or symptomatic bradycardia; 
• resting systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
• resting diastolic blood pressure less than 65 mmHg; 
• resting blood pressure greater than 155/95 mmHg; or 
• prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the above 
criteria, the value should be confirmed by repeating the measurement 
(twice, if necessary).  If 2 of 3 values meet the above criteria, the subject 
will be excluded from participation. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 129


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 9 of 113 
Exclusion 
Criteria 
(continued) 
7. To avoid drug-drug interactions, subjects requiring the following will be 
excluded: 
• 
tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and 
• 
beta-receptor blockers, to avoid the risk of excessive bradycardia. 
N 
Total enrollment will depend on subject drop-out rates.  Approximately 
250 to 500 subjects:  enrollment will continue until a minimum total of 300 
subjects (across this protocol and earlier lofexidine clinical studies expected 
to meet FDA safety database requirements) have been treated with clinically 
relevant doses of lofexidine for a minimum of 7 days.  A target of at least 
50 subjects each treated for clinical scenarios involving methadone or 
buprenorphine treatment will be enrolled (i.e., a total of 50 subjects 
receiving full or partial dose reduction from methadone, methadone-assisted 
withdrawal, and other methadone treatment scenarios and a total of 50 
subjects receiving full or partial dose reduction from buprenorphine, 
transition to buprenorphine maintenance, and other buprenorphine treatment 
scenarios). 
Safety 
Endpoints 
• Occurrence, seriousness, severity, and causality assessment of adverse 
events (AEs). 
• Occurrence of AEs of special interest (i.e., orthostatic hypotension, 
orthostatic bradycardia, syncope). 
• Occurrence of AEs not related to opioid withdrawal. 
• Descriptive evaluation of vital signs (actual and change from baseline) 
for each time point. 
• Descriptive evaluation of the three C-SSRS subscales (suicidal ideation, 
suicidal behavior, and intensity of suicidal ideation). 
• Shifts from baseline in physical examination findings. 
• Descriptive evaluation of clinical laboratory tests of hematology, 
chemistry, and urinalysis (actual and change from baseline).   
• Descriptive evaluation of ECG (actual and change from baseline). 
Effectiveness 
Endpoints 
• Number/proportion of subjects successfully completing their pre-defined 
withdrawal treatment goal (e.g., planned detoxification/ transition) as 
assessed by the Principal Investigator. 
• Distribution of number of days required to complete withdrawal 
treatment goal by category. 
• Descriptive evaluation of SOWS-Gossop. 
• Descriptive evaluation of COWS numerical score and severity score 
(i.e., mild, moderate, moderately severe, severe). 
• Concomitant medication analysis. 
• Evaluation of subject treatment status 30 days after last dose. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 130


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 10 of 113 
Duration 
23 days (maximum duration per subject, including screening) 
Visits 
All subjects will undergo screening up to 9 days before study admission. 
Days 1-3 
• In-clinic setting: Subjects may be admitted to the clinic on Day -1. 
Days 4-7 
• In-clinic setting OR daily visits for 4 days if outpatient 
Days 8-14 
• Daily outpatient visits for up 7 days 
Day 30 
• Telephone follow-up contact 
Safety 
Assessments 
The following safety assessments will be performed daily unless otherwise 
specified below: 
• Occurrence, seriousness, severity, and causality assessment of AEs; 
• Vital signs during in-clinic treatment (Days 1-3 mandatory; Days 4-7 if 
subject receives all lofexidine doses in the clinic), including blood 
pressure and pulse at rest (sitting [or recumbent if necessary because of 
an adverse event]) and standing (if able) before every dose and 3.5 hours 
after administration of study medication at 8 AM, 1 PM, and 6 PM 
(respiration and temperature before 8 AM dose only); 
• Vital signs during outpatient treatment (Days 4-7 optional; Days 8-14 if 
subject continues taking lofexidine), including blood pressure and pulse 
at rest (sitting [or recumbent if necessary because of an adverse event]) 
and standing (if able) at least once daily before dosing and 3.5 hours 
after dosing on Days 4-13 and once before any dose on Day 14 or, if 
applicable, at discontinuation from the study (note: if subjects cannot 
stay in the clinic for measurement of the 3.5-hour post-dose vital signs, 
they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point, with values 
recorded in a subject diary); 
• 12-lead ECGs (in duplicate) recorded as follows: 
 Day 1 before the first dose at 8 AM and at 3.5 hours after dosing; 
 Before subject’s last dose and after dosing or, if applicable, at 
discontinuation from the study; 
• Clinical laboratory tests as clinically warranted and at discontinuation 
from the study;  
• Complete physical examination 3 to 4 hours after first dose on Day 1, as 
clinically warranted, and at discontinuation from the study; 
• Pregnancy test at discontinuation from the study; 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 131


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 11 of 113 
Safety 
Assessments 
(continued) 
• C-SSRS 3.5 hours after the first dose (8 AM) during in-clinic treatment, 
once daily before dosing during outpatient treatment, or, if applicable, at 
discontinuation from the study; 
• A qualitative urine drug screening (by on-site use of “dipsticks”) for 
specific drug or metabolite classification will be done every day during 
in-clinic treatment to monitor for contraband and every day during 
outpatient treatment to monitor for illicit drug use; 
• A fingerprick blood sample for pharmacokinetic (PK) analysis will be 
collected concurrently with each scheduled ECG; and 
• A fingerprick blood sample will be collected during outpatient treatment 
when the subject reports to the clinic each day (before next scheduled 
dose) for analysis of plasma lofexidine concentration to monitor 
compliance. 
A follow-up telephone contact will be attempted 30 days after the subject’s 
last dose of study drug for an adverse event evaluation and an evaluation of 
the subject’s current treatment status (e.g., relapse, current psychosocial 
treatment, successful entry into a methadone, buprenorphine, or naltrexone 
program). 
Effectiveness 
Assessments 
The following effectiveness assessments will be performed daily unless 
otherwise specified below: 
• SOWS-Gossop 3.5 hours after the first daily dose during in-clinic 
treatment; once daily before dosing during outpatient treatment; 
• COWS 3.5 hours after the first daily dose during in-clinic treatment; 
once daily before dosing during outpatient treatment; 
• Completion of withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator;  
• Concomitant medication use; and 
• Evaluation of subject treatment status 30 days after last dose. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 132


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 12 of 113 
4 TABLE OF CONTENTS 
1 
SIGNATURE PAGE .......................................................................................................2 
2 
PROTOCOL AMENDMENT SUMMARY ...................................................................3 
3 
SYNOPSIS ......................................................................................................................6 
4 
TABLE OF CONTENTS ..............................................................................................12 
5 
ABBREVIATIONS AND DEFINITION OF TERMS .................................................16 
6 
BACKGROUND AND SIGNIFICANCE ....................................................................18 
6.1 
Opioid Dependence ..................................................................................................18 
6.2 
Lofexidine Hydrochloride ........................................................................................18 
6.3 
Efficacy of Lofexidine .............................................................................................19 
6.4 
Safety of Lofexidine .................................................................................................20 
6.5 
Rationale for Dose Selection and Regimen ..............................................................21 
6.6 
Rationale for Outcome Measures .............................................................................21 
7 
STUDY OBJECTIVES .................................................................................................22 
8 
STUDY SPONSOR ......................................................................................................22 
9 
STUDY SITES AND INVESTIGATORS ...................................................................22 
10 
INVESTIGATIONAL PLAN .......................................................................................22 
10.1 
Overall Design ..........................................................................................................22 
10.2 
Number of Subjects ..................................................................................................23 
10.3 
Duration of Study .....................................................................................................23 
10.4 
Dose Hold and Discontinuation Criteria (2 of 3 Rule) .............................................23 
11 
SELECTION OF STUDY POPULATION ..................................................................24 
11.1 
Population Base ........................................................................................................24 
11.2 
Study Entrance Requirements ..................................................................................24 
11.2.1 
Inclusion Criteria .................................................................................................24 
11.2.2 
Exclusion Criteria ................................................................................................25 
11.3 
Screening Failures ....................................................................................................27 
12 
INVESTIGATIONAL AGENTS ..................................................................................27 
12.1 
Lofexidine Hydrochloride ........................................................................................27 
12.2 
Dispensing Investigational Agent ............................................................................27 
12.3 
Blinding Plan ............................................................................................................28 
12.4 
Labeling ....................................................................................................................28 
12.5 
Storage ......................................................................................................................28 
12.6 
Record of Administration .........................................................................................28 
12.7 
Used/Unused Supplies ..............................................................................................29 
12.8 
Contraindications .....................................................................................................29 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 133


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 13 of 113 
13 
TREATMENT PLAN ...................................................................................................29 
13.1 
Investigational Agent ...............................................................................................29 
13.2 
Dose Administration ................................................................................................29 
13.2.1 
Administration of Doses ......................................................................................29 
13.2.2 
Dose Hold Criteria ...............................................................................................30 
13.2.3 
Discontinuation Criteria ......................................................................................31 
13.3 
Treatment Compliance .............................................................................................32 
13.4 
Nicotine Replacement Therapy ................................................................................33 
14 
STUDY PROCEDURES ..............................................................................................33 
14.1 
Subject Recruitment and Consent ............................................................................33 
14.2 
Screening ..................................................................................................................34 
14.3 
Treatment Phase .......................................................................................................34 
14.3.1 
Days 1-3 (Mandatory In-clinic) ...........................................................................34 
14.3.2 
Days 4-7 (In-clinic/Outpatient) ...........................................................................34 
14.3.3 
Days 8-14 (Outpatient Only) ...............................................................................34 
14.4 
Subject Reimbursement ............................................................................................35 
14.5 
Study Discontinuation ..............................................................................................35 
14.5.1 
Subject Discontinuation .......................................................................................35 
14.5.2 
Cardiovascular Events Requiring Subject Discontinuation From Study ............36 
14.5.3 
Trial Discontinuation ...........................................................................................37 
14.6 
Concomitant Therapy ...............................................................................................37 
15 
CLINICAL EVALUATIONS .......................................................................................38 
15.1 
Screening Assessments ............................................................................................41 
15.2 
Baseline Assessments ...............................................................................................42 
15.3 
Assessments During Treatment ................................................................................42 
15.3.1 
Days 1-3 (Mandatory In-clinic) ...........................................................................42 
15.3.2 
Days 4-7 (In-clinic/Outpatient) ...........................................................................43 
15.3.3 
Days 8-14 (Outpatient Only) ...............................................................................44 
15.3.4 
Study Discontinuation/End of Study ...................................................................45 
15.3.5 
30-Day Telephone Follow-up Contact ................................................................46
15.4 
Effectiveness Assessment Methods .........................................................................46 
15.4.1 
Assessment of Completion of Pre-Defined Withdrawal Treatment Goal ...........46 
15.4.2 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) ..............................46 
15.4.3 
Clinical Opiate Withdrawal Scale (COWS) ........................................................47 
15.5 
Safety Assessment Methods .....................................................................................47 
15.5.1 
Adverse Events ....................................................................................................47 
15.5.1.1 
Withdrawal-Related Adverse Events ..............................................................48 
15.5.2 
Vital Signs ...........................................................................................................48 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 134


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 14 of 113 
15.5.3 
12-Lead Electrocardiograms ...............................................................................49 
15.5.4 
Clinical Laboratory Evaluations ..........................................................................50 
15.5.4.1 
Standard Laboratory Tests ..............................................................................50 
15.5.4.2 
Infectious Disease Panel and Syphilis Tests ...................................................51 
15.5.4.3 
Urine Toxicology Screening ...........................................................................52 
15.5.4.4 
Pregnancy Test ................................................................................................52 
15.5.4.5 
Pharmacokinetic Sampling .............................................................................52 
15.5.5 
Physical Examination ..........................................................................................52 
15.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................52 
15.6 
Other Assessments ...................................................................................................53 
15.6.1 
Prior Medications ................................................................................................53 
15.6.2 
Concomitant Medication Administration ............................................................53 
16 
REGULATORY AND REPORTING REQUIREMENTS ...........................................53 
16.1 
Good Clinical Practices ............................................................................................53 
16.2 
FDA Forms 1572 and Financial Disclosure .............................................................53 
16.3 
Institutional Review Board Approval ......................................................................54 
16.4 
Informed Consent/HIPAA Authorization ................................................................54 
16.5 
Drug Accountability .................................................................................................54 
16.6 
Outside Monitoring ..................................................................................................55 
16.6.1 
Medical Monitor ..................................................................................................55 
16.6.2 
Clinical Monitors .................................................................................................55 
16.7 
Adverse Event Reporting .........................................................................................56 
16.8 
Serious Adverse Events (SAEs) ...............................................................................56 
16.9 
Pregnancy .................................................................................................................57 
17 
STATISTICAL APPROACH .......................................................................................58 
17.1 
General Considerations ............................................................................................58 
17.2 
Assessment of Effectiveness ....................................................................................58 
17.3 
Assessment of Safety ...............................................................................................59 
18 
DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) ............................59 
18.1 
Data Collection .........................................................................................................59 
18.2 
Electronic Data Capture ...........................................................................................60 
18.3 
Data Analysis ...........................................................................................................60 
18.4 
Study Documentation and Records Retention .........................................................60 
18.5 
Confidentiality ..........................................................................................................61 
18.5.1 
Confidentiality of Data ........................................................................................61 
18.5.2 
Confidentiality of Subject Records .....................................................................61 
19 
DISSEMINATION AND PUBLICATION OF STUDY RESULTS ...........................61 
20 
PROTOCOL ADHERENCE AND AMENDMENTS..................................................62 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 135


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 15 of 113 
21 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................62 
22 
REFERENCES ..............................................................................................................62 
23 
PROTOCOL AMENDMENT DETAILS .....................................................................64 
TABLES 
Table 1. Schedule of Study Assessments .............................................................................39 
Table 2. SOWS-Gossop Scoring Method ............................................................................47 
Table 3. Hematology, Chemistry, and Urinalysis Tests ......................................................51 
Table 4. Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    
USWM-LX1-3003-2, Amendment No. 01 (January 22, 2015) .............................65 
APPENDICES 
Appendix 1 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
Appendix 2 
Clinical Opiate Withdrawal Scale (COWS) 
Appendix 3 
Subject Diary 
Appendix 4 
Short-term Withdrawal Treatment Goal 
Appendix 5 
Columbia Suicide Severity Rating Scale (C-SSRS) Baseline Version 
Appendix 6 
Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version 
Appendix 7 
Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events 
Appendix 8 
Procedure for Applying for a Certificate of Confidentiality 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 136


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 16 of 113 
5 ABBREVIATIONS AND DEFINITION OF TERMS 
Abs 
Absolute 
AE(s) 
Adverse Event(s) 
AIDS 
Acquired Immune Deficiency Syndrome 
ALT/SGPT 
Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
Anti-HCV 
Hepatitis C Virus Antibody 
aPTT 
Activated Partial Thromboplastin Time 
AST/SGOT 
Aspartate Aminotransferase/Serum Glutamic-Oxaloacetic 
Transaminase 
BP 
Blood Pressure 
bpm 
beats per minute 
BUN 
Blood Urea Nitrogen 
CAP 
College of American Pathologists 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act of 1988 
CO2 
Carbon Dioxide 
COWS 
Clinical Opiate Withdrawal Scale 
CRF(s) 
Case Report Form(s) 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DAWN 
Drug Abuse Warning Network 
DBP/dBP 
Diastolic Blood Pressure 
DHHS 
Department of Health and Human Services 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders - Fourth 
Edition 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EIA 
Enzyme Immunoassay 
eCRF(s) 
Electronic Case Report Form(s) 
ED 
Emergency Department 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
Gamma-Glutamyl Transpeptidase 
GI 
Gastrointestinal 
HBcAb 
Hepatitis B Core Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 137


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 17 of 113 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MHOWS 
Modified Himmelsbach Opiate Withdrawal Scale 
M.I.N.I.
Mini International Neuropsychiatric Interview 
mmHg
Millimeters of Mercury 
msec
Millisecond 
NSAIDs
Nonsteroidal anti-inflammatory drugs 
NDA
New Drug Application 
NIMH
National Institute of Mental Health 
OL
Open Label 
PK
Pharmacokinetic 
PP
Per Protocol 
PPD
Purified Protein Derivative (skin test for tuberculosis) 
PT
Prothrombin Time 
QID
Four Times Daily 
QT
QT interval of an electrocardiogram 
QTc
Corrected QT interval 
QTcB
Corrected QT interval – Bazett’s method 
QTcF
Corrected QT interval – Fridericia’s method 
QTcI
Subject-specific QT 
RBC
Red Blood Cell 
RBM
Risk Based Monitoring 
RDW
Red Blood Cell Distribution Width 
RPR
Rapid Plasma Reagin 
SAE(s)
Serious Adverse Event(s) 
SAP
Statistical Analysis Plan 
SBP/sBP
Systolic Blood Pressure 
SOWS-Gossop
Short Opiate Withdrawal Scale of Gossop 
TEAEs
Treatment-Emergent Adverse Events 
T4
Free Thyroxine 
Tmax
Time of Maximum Plasma Drug Concentration 
TPPA
Treponema Pallidum Particle Agglutination Assay 
TSH
Thyroid-Stimulating Hormone 
UDS
Urine Drug Screening 
UK
United Kingdom 
ULN
Upper Limit of Normal 
US
United States 
USWM
US WorldMeds, LLC 
WBC
White Blood Cell 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 138


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 18 of 113 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 139


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 19 of 113 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 140


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
 
Page 20 of 113 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 141


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
 
Page 21 of 113 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 142


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 22 of 113 
7 STUDY OBJECTIVES 
The primary objective is to continue to investigate the safety of lofexidine when administered 
for at least 7 days at clinically relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms of 
acute withdrawal from opioids in a variety of clinical scenarios in both in-clinic and 
outpatient settings.  The effectiveness of lofexidine is also of interest.   
8 STUDY SPONSOR 
This study will be conducted under an Investigational New Drug (IND) application (#47,857) 
held by US WorldMeds, LLC. 
9 STUDY SITES AND INVESTIGATORS 
This study will be conducted at approximately 20 study sites in the US.  It is the 
responsibility of the Principal Investigators to make sure this protocol is conducted in full 
conformance with the ethical principles detailed in Section 16 of this protocol.  All data will 
be collected at the study sites on source documents and entered at the site into electronic case 
report forms (eCRFs) as described in Section 18.1 of this protocol. 
10 INVESTIGATIONAL PLAN 
10.1 Overall Design 
This is a Phase 3, multicenter, open-label study to evaluate the safety and effectiveness of 
lofexidine in alleviation of withdrawal signs and symptoms in subjects undergoing 
abstinence from any opioid, including methadone and buprenorphine maintenance treatment, 
which would likely require at least 7 days of lofexidine treatment for alleviation of 
withdrawal.  Any subject seeking treatment for partial or total opioid withdrawal will be 
eligible.  This can include a variety of clinical situations where opioid withdrawal illness is 
likely to occur, such as (but not limited to) abrupt and total withdrawal (including from 
methadone and buprenorphine), agonist-assisted total withdrawal, dose reduction of 
maintenance treatment (e.g., methadone, buprenorphine), and transition from an opioid 
agonist to naltrexone or buprenorphine maintenance.  Subjects will be evaluated for their 
compliance with protocol inclusion/exclusion criteria during a screening period, lasting up to 
9 days.  Approximately 250 to 500 subjects will receive lofexidine treatment for 7 days, 
starting at a dose of 3.2 mg daily (0.8 mg QID), with lowering of the dose allowed to 2.4 mg 
daily (0.6 mg QID) if required for tolerability based on the subject’s individual treatment 
goal and response per clinical judgment of the Principal Investigator.  Lofexidine 
administration should be initiated in concurrence with the change in opioid dose which is 
anticipated to elicit withdrawal symptoms (e.g., first day of dose reduction, or first day of 
abrupt cessation) or on the first day of emergence/anticipated emergence of such symptoms 
as determined at the Investigator’s discretion.  Details regarding the timing of lofexidine 
therapy initiation relative to change in opioid dose and onset/expected onset of symptoms 
should be captured in the source.  All subjects will receive all 4 doses of lofexidine in a clinic 
setting for the first 3 days (Days 1-3) and then, per clinical judgment of the Principal 
Investigator, subjects can continue to receive lofexidine doses in a clinic setting or can be 
treated outside of the clinic (outpatient) for the remaining 4 days of mandatory lofexidine 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 143


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 23 of 113 
treatment (Days 4-7).  Per Principal Investigator judgment, subjects can continue lofexidine 
treatment beyond Day 7 on an outpatient basis only for up to an additional 7 days 
(Days 8-14).  Note that lofexidine dosing may be stopped at any time during Days 8-14.  No 
subject will receive lofexidine for more than 14 days total.  All subjects receiving lofexidine 
treatment on an outpatient basis will be required to return to the clinic daily to undergo 
specific assessments (including qualitative urine drug screening) as listed in Table 1 of 
Section 15. 
10.2 Number of Subjects 
The total enrollment in this study will depend on subject drop-out rates in this protocol.  
Enrollment will continue until a minimum total of 300 subjects (across this protocol and 
earlier lofexidine clinical studies expected to meet FDA safety database requirements) have 
been treated with clinically relevant doses of lofexidine for a minimum of 7 days.  It is 
estimated that approximately 250 to 500 subjects will be enrolled in this open-label study in 
order to accrue a sufficiently large safety database for evaluation.   
10.3 Duration of Study 
This study will be initiated after completion of the companion study, USWM-LX1-3003-1.  
The maximum duration of participation for each subject in USWM-LX1-3003-2 will be 
23 days, including the Screening period, which can last up to 9 days, followed by up to 
14 days of treatment with lofexidine. 
The study will be terminated when the database is judged to be sufficient, i.e., a minimum of 
300 subjects (across this protocol and earlier lofexidine clinical studies expected to meet 
FDA safety database requirements) have been treated with clinically relevant doses of 
lofexidine for a minimum of 7 days.  Enrollment is anticipated to take 4 to 10 months to 
achieve, with the total clinical duration of USWM-LX1-3003-2 anticipated to be 8 to 
12 months. 
10.4 Dose Hold and Discontinuation Criteria (2 of 3 Rule) 
When a blood pressure, heart rate, or QTcF interval value meets criteria for withholding a 
dose (Section 13.2.2) or discontinuation from the study (Section 13.2.3), the value needs to 
be confirmed by the site personnel by repeating the vital sign measurement or ECG 
recording, approximately 10 to 15 minutes later.  If the value is confirmed by the second 
measurement, the appropriate action will be taken (dose hold or study discontinuation) and 
the confirmatory value will be recorded in the subject’s source document and appropriate 
eCRF.  If the second value does not meet the specified criteria, a third measurement will be 
taken approximately 10 to 15 minutes later.  If this value is confirmatory, the appropriate 
action will be taken (dose hold or study discontinuation) and the last confirmatory value will 
be recorded in the subject’s source document and appropriate eCRF.  If the third value does 
not confirm the initial finding, then no action should be taken and the third value should be 
entered in the subject’s source and appropriate eCRF. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 144


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 24 of 113 
Whenever blood pressure, heart rate, or QTcF interval values meet dose hold or study 
discontinuation criteria, these are to be recorded on the subject’s eCRF as an adverse event 
(AE) or serious adverse event (SAE), as applicable.  Examples are: 
Item 
Record Adverse Event of: 
Resting Vital Signs 
 
SBP <90 mmHg and >20% below screen value 
Hypotension 
DBP <50 mmHg and >20% below screen value 
Hypotension 
Pulse <50 bpm and >20% below screen value 
Bradycardia 
Orthostatic Vital Signs 
 
SBP >25% below recumbent values 
Postural hypotension 
DBP <25% below recumbent values 
Postural hypotension 
Pulse >25% below recumbent values 
Postural bradycardia 
DBP = diastolic blood pressure, SBP = systolic blood pressure 
 
11 SELECTION OF STUDY POPULATION 
11.1 Population Base 
Any opioid-dependent subject about to undergo complete or partial opioid withdrawal and 
could benefit for a minimum of a 7-day treatment with lofexidine will be eligible for the 
study.  Entry into this study is open to both men and women and to all racial and ethnic 
subgroups.  An attempt will be made to include at least 25% female subjects, a mix of 
ethnicities reflecting the distribution in the local geographic regions of the study sites, and a 
minimum of 50 subjects each on methadone or buprenorphine maintenance treatment.  
Subjects will be recruited from a variety of sources, including subjects seeking treatment for 
opioid dependence via referrals from local treatment providers, word of mouth among 
subjects themselves also seeking treatment, and advertising in the local media.  Recruitment 
advertisements will be approved by each site’s Institutional Review Board (IRB). 
Potential subjects may be accepted for screening after the nature and purpose of the 
investigation have been explained to them and after they have voluntarily given written 
informed consent (see Section 16.4). 
11.2 Study Entrance Requirements 
11.2.1 Inclusion Criteria 
To be eligible for participation, subjects must meet all of the following criteria: 
1. Be able to verbalize understanding of the consent form, able to provide written 
informed consent, and verbalize willingness to complete study procedures. 
2. Be male or female at least 18 years of age. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 145


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 25 of 113 
3. Have current dependence, according to the Mini International Neuropsychiatric 
Interview (M.I.N.I.) [18, 19], on any opioid (including methadone and buprenorphine 
maintenance treatment). 
4. Be seeking treatment for partial or total withdrawal from current opioid and expected, 
as determined by the Principal Investigator, to benefit from lofexidine treatment for at 
least 7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This can include a 
variety of clinical situations where opioid withdrawal illness is likely to occur.  
Examples include: 
• abrupt and total withdrawal (including from methadone and buprenorphine); 
• agonist-assisted total withdrawal; 
• dose reduction of maintenance treatment (e.g., methadone, buprenorphine); and 
• transition from an opioid agonist to naltrexone or buprenorphine maintenance. 
5. Urine toxicology screen positive for opioid(s) relevant to the subject’s withdrawal 
treatment goal (can include methadone and buprenorphine) at Screening. 
6. If female and of childbearing potential, subject must agree to use of one of the 
following methods of birth control: 
• oral contraceptives; 
• patch; 
• barrier (diaphragm, sponge or condom) plus spermicidal preparations; 
• intrauterine contraceptive system; 
• levonorgestrel implant; 
• medroxyprogesterone acetate contraceptive injection; 
• complete abstinence from sexual intercourse; 
• hormonal vaginal contraceptive ring; or 
• surgical sterilization or partner sterile (must have had documented proof). 
11.2.2 Exclusion Criteria 
Subjects who meet any of the following criteria will not be allowed to participate: 
1. Be a female subject who is pregnant or lactating. 
2. Have a very serious medical illness not under control as detailed below. 
• Serious medical illness will be determined at Screening by: 
 medical history; 
 physical examination; 
 12-lead electrocardiogram (duplicate); 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 146


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 26 of 113 
 clinical laboratory tests, including standard lab tests, an infectious disease 
panel for syphilis (excluded if positive), hepatitis (positive results do not 
exclude a prospective subject from participation unless there is an indication 
of active liver disease), and hepatitis (positive results do not exclude a 
prospective subject from participation unless there is an indication of active 
liver disease); and 
 tuberculin test (purified protein derivative [PPD]) and/or a chest x-ray (a 
positive PPD result does not exclude a prospective subject from participation, 
but if diagnostic tests [e.g., chest x-ray] indicate that active disease is present, 
the subject will be excluded from participation). 
• Have active self-reported acquired immune deficiency syndrome (AIDS) or self-
reported human immunodeficiency virus (HIV) positive status and taking 
retroviral medications currently or within the past 4 weeks. 
• Have an unstable psychiatric condition (e.g., suicide risk, per Investigator 
judgment). 
3. Current dependence (based on the M.I.N.I.) on any psychoactive substance 
(excluding caffeine, nicotine, and the subject’s current opioid-dependence agent, 
which can include methadone and buprenorphine, for example, in agonist-maintained 
subjects) that requires detoxification or dose reduction as part of the pre-defined 
individual subject withdrawal treatment goal. 
4. Have participated in an investigational drug study within the past 30 days. 
5. Have history of lofexidine exposure in a prior clinical trial or otherwise. 
6. Abnormal cardiovascular exam at screening, including any of the following: 
• clinically significant abnormal electrocardiogram (ECG) (e.g., second or third 
degree heart block, uncontrolled arrhythmia, or QTcF intervals greater than 
450 msec for males and greater than 470 msec for females); 
• resting pulse less than 55 bpm or symptomatic bradycardia; 
• resting systolic blood pressure less than 95 mmHg or symptomatic hypotension; 
• resting diastolic blood pressure less than 65 mmHg; 
• resting blood pressure greater than 155/95 mmHg; or 
• prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the above criteria, the 
value should be confirmed by repeating the measurement (twice, if necessary).  If 2 of 
3 values meet the above criteria, the subject will be excluded from participation. 
7. To avoid drug-drug interactions, subjects requiring the following will be excluded: 
• tricyclic antidepressants, which may reduce the efficacy of imidazoline 
derivatives; and 
• beta-receptor blockers, to avoid the risk of excessive bradycardia. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 147


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 27 of 113 
11.3 Screening Failures 
Screening failures are potential study subjects who provide informed consent and fail 
inclusion and/or exclusion criteria or for other reasons are not allowed to participate.  A 
screening log for all subjects who are screened will be maintained.  The screening log will 
uniquely identify each subject and report whether he or she passed or failed screening, and, if 
he or she did not pass, the reasons for the screening failure. 
12 INVESTIGATIONAL AGENTS 
12.1 Lofexidine Hydrochloride 
Lofexidine hydrochloride is an α2-adrenergic agonist with mild to moderate antihypertensive 
actions.  It has the empirical formula C11H13Cl3N2O representing a molecular weight of 
295.61.  The structural formula is: 
 
Lofexidine hydrochloride is a synthetic product and has the chemical designation of 2-[1-
(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride.  It is a white to 
off-white crystalline powder that is very soluble in water and ethanol.  It is lightly soluble in 
2-propanol and practically insoluble in ether.  Lofexidine hydrochloride melts at 
approximately 126-128°C. 
Lofexidine will be supplied by the Sponsor (USWM) in peach colored tablets containing 
0.2 mg of active medication for oral administration. 
12.2 Dispensing Investigational Agent 
Lofexidine will be packaged and distributed through the pharmacy coordinating center 
(Sharp).  Lofexidine tablets will be supplied in uniquely-identified 80-count bottles.  During 
in-clinic treatment, lofexidine doses will be dispensed directly from the 80-count bottles, 
whereas for outpatient treatment doses will be dispensed by the study pharmacist as 
determined clinically appropriate by the Principal Investigator or designee to the subject in 
individual prescription bottles.  One to 2 days of medication may be dispensed at each daily 
clinic visit to accommodate flexible scheduling (e.g., day and a half worth of medication to 
supply subject from one morning to the next afternoon depending on availability for clinic 
visit).  The site will maintain a dispensing log for each bottle and document the number of 
tablets dispensed to each subject along with the number of tablets returned, if any, by the 
subject at each outpatient visit.  Returned tablets will not be re-dispensed to future subjects. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 148


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 28 of 113 
All study medication will be dispensed by the site pharmacist or designee. 
12.3 Blinding Plan 
This is an open-label study. 
12.4 Labeling 
The investigational agent, lofexidine, will be packaged in labeled bottles (80 count pills) and 
during the outpatient portion of the study dispensed to subjects in labeled prescription bottles 
(i.e., redispensing container).  The product label will include the sponsor’s name, protocol 
number, the number of tablets in the bottle, address, 24-hour emergency phone number, and 
the following statement – “Caution: New Drug – Limited by Federal Law to Investigational 
Use.” 
During outpatient treatment (Days 4-14), sites may dispense 1 to 2 days of medication at 
each daily clinic visit to accommodate flexible scheduling for use in an outpatient setting 
(e.g., day and a half worth of medication to supply subject from one morning to the next 
afternoon depending on availability for clinic visit).  In such cases, the redispensing container 
will include a subject label, supplied by the study site, and will include the following 
information: 
• Principal Investigator’s name and number, 
• Subject number, 
• Date of dispensing, 
• Directions for use, 
• Drug name / dose or protocol number, 
• Number of pills dispensed, 
• Sponsor’s name, and 
• For Investigational Use Only. 
12.5 Storage 
The investigational agent, lofexidine, will be stored at 68-77°F in a secure location at the 
dispensing pharmacy or site.  Temperature of the investigational agent will be maintained at 
68-77°F during transport.  Temperature of the investigational agent will be monitored during 
storage and transport.  Temperature excursions will be reported to the Sponsor and the 
Sponsor will determine if the investigational agent is fit for use. 
12.6 Record of Administration 
Accurate recording of all investigational agent received, dispensed, administered, and 
returned will be maintained by study site personnel.  During outpatient treatment 
(Days 4-14), subjects are to record doses taken in his/her subject diary. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 149


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 29 of 113 
12.7 Used/Unused Supplies 
Unused investigational agent will be retained at the participating sites to enable a full 
investigational drug inventory by the sites’ respective monitor.  If any investigational agent is 
lost or damaged, its disposition should be documented.  The Sponsor will provide 
instructions to return the unused study drug to the pharmacy coordinating center periodically 
throughout the study (following monitor review) or at the end of the study for proper 
destruction in accordance with local and federal regulations. 
12.8 Contraindications 
Clonidine is specifically prohibited in this study. 
To avoid drug-drug interactions, lofexidine should not be administered concurrently with: 
• 
tricyclic antidepressants – may reduce the efficacy of imidazoline derivatives; and 
• 
beta-receptor blockers – the combination of lofexidine and beta-receptor blockers 
should be used with caution to avoid the risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug therapy and appropriate caution 
is warranted in subjects on such therapy.  The Principal Investigator may need to lower the 
subject’s antihypertensive dose during the study. 
Lofexidine should generally not be administered concurrently with alcohol, sedatives, and 
anesthetics as these may interact with lofexidine and enhance its central sedative effects. 
13 TREATMENT PLAN 
13.1 Investigational Agent 
All subjects in this study will receive lofexidine, as described in Section 13.2. 
13.2 Dose Administration 
13.2.1 Administration of Doses 
Lofexidine administration should be initiated in concurrence with the change in opioid dose 
which is anticipated to elicit withdrawal symptoms (e.g., first day of dose reduction, or first 
day of abrupt cessation) or on the first day of emergence/anticipated emergence of such 
symptoms as determined at the Investigator’s discretion.  Details regarding the timing of 
lofexidine therapy initiation relative to change in opioid dose and onset/expected onset of 
symptoms should be captured in the source.  All subjects will take lofexidine orally for 
7 days, starting on Day 1 at a dose of 3.2 mg per day (0.8 mg QID), with lowering of the 
dose allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the subject’s 
individual treatment goal and response per clinical judgment of the Principal Investigator.  
The subject’s dose may be changed back to 3.2 mg/day, per Principal Investigator judgment, 
but in no case is the dose of lofexidine to exceed 3.2 mg/day (or a single dose of 0.8 mg).  
Supporting rationale for any dose changes must be recorded in the subject’s source 
document. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 150


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 30 of 113 
All subjects will receive all 4 doses of lofexidine in a clinic setting for the first 3 days 
(Days 1-3) and then, per clinical judgment of the Principal Investigator, subjects can continue 
to receive lofexidine doses in a clinic setting or can be treated outside of the clinic 
(outpatient) for the remaining 4 days of mandatory lofexidine treatment (Days 4-7).  Note 
that the decision to allow outpatient treatment should take into account the subject’s 
sensitivity to the hypotensive effects of the study medication (as observed over Days 1-3) and 
the subject’s potential for noncompliance.  Furthermore, the rationale for the decision to 
continue treatment through either an in-clinic or outpatient setting must be documented in the 
subject’s source document.   
During in-clinic treatment, subjects must take lofexidine within a 1-hour window, 30 minutes 
before or after 8 AM and within a 30-minute window, 15 minutes before or after 1 PM, 
6 PM, and 11 PM, with the actual date and time of each dose recorded in the subject’s source 
document and in the eCRF.  For subjects receiving outpatient treatment (elective) on 
Days 4-7 and those continuing optional lofexidine treatment in an outpatient setting for up to 
an additional 7 days (Days 8-14), prescribed dosing will remain on the same QID schedule 
(8 AM, 1 PM, 6 PM, 11 PM) with compliance assessed at the next day’s clinic visit by pill 
count, subject report of dosing in diary (Appendix 3), and a fingerprick blood sample to 
assess plasma lofexidine concentrations. 
Optional Outpatient Treatment (Days 8-14) 
Per Principal Investigator judgment, subjects can continue lofexidine treatment on an 
outpatient basis for up to an additional 7 days, per the dose schedule listed below.  The 
rationale for the decision to continue lofexidine treatment must be documented in the 
subject’s source document.  Note that lofexidine dosing may be stopped at any time during 
Days 8-14.  No subject will receive lofexidine for more than 14 days total in this study. 
 
If Dose Regimen on Day 7 is 
If Dose Regimen on Day 7 is 
Day 
3.2 mg/day (0.8 mg QID) 
2.4 mg/day (0.6 mg QID) 
8 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
9 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
10 
2.4 mg/day (0.6 mg QID) 
1.6 mg/day (0.4 mg QID) 
11 
1.6 mg/day (0.4 mg QID) 
0.8 mg/day (0.2 mg QID) 
12 
1.6 mg/day (0.4 mg QID) 
0.8 mg/day (0.2 mg QID) 
13 
0.8 mg/day (0.2 mg QID) 
0.8 mg/day (0.2 mg QID) 
14 
0.8 mg/day (0.2 mg QID) 
0.8 mg/day (0.2 mg QID) 
 
Note:  In order to prevent dehydration from opioid withdrawal, increased fluid intake will be 
encouraged from the beginning of the study. 
13.2.2 Dose Hold Criteria 
Study medication will be held if pre-dose vital signs meet any of the criteria listed below (see 
Section 10.4 for details on repeat confirmatory requirements). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 151


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 31 of 113 
Resting (sitting [or recumbent if necessary because of an AE]) 
• 
Systolic blood pressure <90 mmHg and >20% below screen value; 
• 
Diastolic blood pressure <50 mmHg and >20% below screen value; 
• 
Pulse <50 bpm and >20% below screen value; or 
• 
Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness). 
Orthostatic (after standing for 3 minutes) 
• 
Systolic blood pressure diastolic blood pressure, or pulse >25% below 
recumbent values. 
During outpatient treatment, if the subject experiences symptoms of hypotension and/or 
bradycardia (see below), he/she should call the study site and the site should instruct the 
subject on whether the next dose should be delayed, skipped, or he/she should be seen in the 
clinic.  The subject should record this information in the subject diary (Appendix 3). 
• marked dizziness 
• fainting (especially when standing from a sitting or lying position) 
• light headedness 
• Fatigue 
• Weakness 
• shortness of breath 
• chest pains 
• easily tiring during physical activity 
• confusion or memory problems 
• blurred vision 
• nausea 
• cold, clammy pale skin 
• rapid shallow breathing 
• depression 
• thirst 
All instances of dose-holds must be clearly documented in the subject’s source document and 
dosing eCRF, and the event causing the dose hold should be recorded on the AE or SAE 
eCRF, as applicable. 
13.2.3 Discontinuation Criteria 
A subject will be discontinued from the study if any of the criteria listed below are met (see 
Section 10.4 for details on repeat confirmatory requirements).  All instances should be 
recorded in the subject’s source document and AE or SAE eCRF, as applicable. 
• 
Resting systolic blood pressure <70 mmHg; 
• 
Resting diastolic blood pressure <40 mmHg; 
• 
Resting pulse <40 bpm; 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 152


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 32 of 113 
• 
QTcF >500 msec1 or >25% above screen value for both males and females; or 
• 
Syncope. 
Additional discontinuation criteria based on cardiovascular events are: 
• New onset of clinically significant abnormal ECG per Investigator judgment 
(e.g., second or third degree heart block or uncontrolled arrhythmia, prolonged 
QTcF interval). 
• Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or 
fluids). 
• Single occurrence of symptomatic bradycardia (as assessed by Principal 
Investigator/study physician/assigned staff, regardless of blood pressure) associated 
with chest pain, shortness of breath, or decreased level of consciousness. 
• Persistent hypertension – resting blood pressure ≥185/110 mmHg recorded on 3 
separate occasions taken at least 5 minutes apart AND within a 1-hour time period.  If 
2 of 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. 
• Medical Intervention for Cardiovascular Event:  Any medical intervention 
(nonmedication or medication inclusive) used for the treatment of any cardiovascular 
event, with the exception of a positional intervention in subjects displaying 
hypotension. 
• Any other clinically significant cardiovascular signs or symptoms that would place the 
subject at risk. 
• Subject misses more than a total of 6 doses during Days 1-7. 
13.3 Treatment Compliance 
All subjects will receive all 4 doses of lofexidine in a clinic setting for the first 3 days of 
lofexidine treatment (Days 1-3) and then, per clinical judgment of the Principal Investigator, 
subjects can continue to receive lofexidine doses in a clinic setting or can be treated outside 
of the clinic (outpatient) for the remaining 4 days of mandatory lofexidine treatment 
(Days 4-7).  Per Principal Investigator judgment, subjects can continue lofexidine treatment 
beyond Day 7 on an outpatient basis only for up to an additional 7 days (Days 8-14).  No 
subject will receive lofexidine for more than 14 days total.  In an in-clinic setting, each dose 
will be observed by study staff and hand and mouth checks will be performed.  In an 
outpatient setting, self-dosing compliance will be evaluated at the next day’s clinic visit by 
pill count, subject report of dosing in diary (Appendix 3), and a fingerprick blood sample to 
assess plasma lofexidine concentrations.  Subjects will be instructed to call the Principal 
Investigator’s office before taking the next dose of study medication if they notice any 
symptoms of hypotension and/or bradycardia (see list in Section 13.2.2), especially when 
                                                 
1 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval.  
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 153


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 33 of 113 
standing from a sitting or lying position.  The study physician or assigned staff will 
determine if the next dose should be delayed, skipped, or the subject should be seen.  Any 
change in prescribed dosing will be recorded and confirmed also by pill count and subject 
report at the next visit. 
13.4 Nicotine Replacement Therapy 
Subjects may be permitted to smoke during their in-clinic participation in study based on 
individual site policy.  If they usually use tobacco products, they will be offered and 
encouraged to use nicotine replacement therapy (patch, gum, inhaler, or nasal spray) while 
they are in the in-clinic facility to treat their nicotine withdrawal symptoms.  If smoking is 
permitted by a participating site, smoking breaks outside of the in-clinic facility must be 
constantly observed and supervised. 
The estimated total number of tobacco products used by subjects per day during in-clinic 
treatment will be recorded in the subject’s source document and on the eCRF. 
14 STUDY PROCEDURES 
14.1 Subject Recruitment and Consent 
Interested subjects, who respond to recruitment materials and are available to stay for the 
mandatory 3-day in-clinic treatment part of the study and available for participation in either 
an in-clinic or outpatient setting for 4 additional days (total commitment of 7 days), will be 
scheduled to meet with a qualified investigative staff member and receive an explanation of 
the study purpose and requirements in lay language.  During the initial interview, the 
interviewer should not ask questions in a manner that reveals the eligibility criteria for study 
entry. 
If still interested after receiving an explanation of the study, a qualified investigative site staff 
member will review the study informed consent form with subjects, and subjects will be 
given an opportunity to review on their own, inquire about, and sign the informed consent 
form (see Section 16.4).  The subject will then be given a copy of the signed consent form.  
After that, subjects will be given a subject number and proceed to the screening phase of the 
study.  Screening assessments must be completed within a 9-day time period, but can be 
completed as early as the first screening day.  At no time during the screening process should 
individuals be given information regarding inclusion or exclusion criteria.  When individuals 
are evaluated, questions should be asked in a way that the criteria are not discernible. 
Any subject who has difficulty understanding the information contained in the consent form 
will reread the misunderstood portion(s) of the consent and discuss with a research staff 
member until s/he shows complete understanding of the information in the consent form, and 
may thus give full consent.  Research staff will work closely with the subject in an effort to 
help them understand the requirements of their participation.  Subjects with literacy problems 
will be assisted to the extent possible. 
Any subject who is unable to demonstrate understanding of the information contained in the 
informed consent will be excluded from study participation and assisted in finding other 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 154


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 34 of 113 
sources of treatment at the subject’s sole expense.  Subjects who are excluded, or who 
decline participation, may be rescreened at a later time, although at least 30 days must occur 
between screenings.  Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
14.2 Screening  
Screening assessments will be conducted as shown in Table 1 (Section 15).  The screening 
period will last up to 9 days during which the subjects must satisfy the eligibility criteria and 
complete all required screening assessments. 
14.3 Treatment Phase 
14.3.1 Days 1-3 (Mandatory In-clinic) 
After a potential participant has completed all screening assessments and has met all 
eligibility criteria to participate in the study, the Principal Investigator or study coordinator 
will arrange for admission to the hospital or clinic in the evening (Day -1) or early morning 
(Day 1) before study drug administration on Day 1.  After all Baseline requirements have 
been completed (Section 15.2), subjects will receive their first dose of lofexidine during the 
8 AM dosing window on Day 1.  Subjects will be dosed 4 times daily from Day 1 through 
Day 3 at 8 AM, 1 PM, 6 PM, and 11 PM.  Vital signs will be recorded within 30 minutes 
before every dose and 3.5 hours (±15 minutes) after the 8 AM, 1 PM, and 6 PM dose.  
12-lead ECGs will also be collected before the first dose on Day 1 (8 AM) and 3.5 hours 
(±15 minutes) after dosing.  Other clinical assessments will be gathered between 11:00 AM 
and noon each day (see a complete list of assessments in Table 1).  These clinical 
assessments are described in detail in Sections 15.3.5 and 15.5. 
14.3.2 Days 4-7 (In-clinic/Outpatient) 
Per clinical judgment of the Principal Investigator, subjects can continue to receive 
lofexidine treatment in a clinic setting or can be treated outside of the clinic (outpatient) for 
the remaining 4 days of mandatory lofexidine treatment (Days 4-7).  Required clinical 
assessments are detailed in Table 1.  All subjects receiving lofexidine treatment on an 
outpatient basis will be required to return to the clinic daily before a scheduled dose for these 
clinical assessments.  Subjects not requiring extended lofexidine treatment can be discharged 
from the study on Day 7 after receipt of at least one dose of study drug and after all end-of-
study procedures have been completed (see Section 15.3.4). 
14.3.3 Days 8-14 (Outpatient Only) 
Per Principal Investigator judgment, subjects can continue lofexidine treatment on an 
outpatient basis for up to an additional 7 days.  Note that lofexidine dosing may be stopped at 
any time during Days 8-14.  No subject will receive lofexidine for more than 14 days total in 
this study.  Subjects will be required to return to the clinic daily before a scheduled dose for 
clinical assessments (see a complete list of assessments in Table 1). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 155


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 35 of 113 
14.4 Subject Reimbursement 
All compensation will be described in the informed consent form used by each site and 
approved by the site’s or central IRB 
. 
14.5 Study Discontinuation 
14.5.1 Subject Discontinuation 
A subject can withdraw his/her consent for participation in the study at any time without 
prejudice.  The Principal Investigator may discontinue a subject if s/he deems it clinically 
appropriate or for any reason.  Additionally, the Principal Investigator must discontinue a 
subject for any of the following reasons: 
1. Cardiovascular events (see Section 14.5.2). 
2. Abnormal vital signs or ECG meeting criteria in Section 13.2.3. 
3. Serious medical problem thought to be related or unrelated to the study medications. 
4. Intercurrent illness or medical complications that, in the opinion of the Principal 
Investigator, preclude safe administration of study medications. 
5. Alcohol or other sedative/hypnotic withdrawal signs and symptoms developing 
following enrollment into the study (Days 1-3). 
6. Requiring therapy with an exclusionary drug. 
7. Lack of compliance with protocol and/or unit procedures. 
Subjects who are removed from study treatment because of AEs or SAEs will be followed 
until they are medically stabilized to the satisfaction of the study physician or assigned staff 
(see Sections 15.5.1, 16.7, and 16.8).  Appropriate safety evaluations will continue to be 
collected until the subject is discharged from the treatment center or the maximum 14-day 
treatment period has expired.  This stabilization can include medically supervised opioid 
withdrawal (involving behavioral therapy, rescue opioid medications, and/or non-opioid 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 156


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 36 of 113 
pharmacotherapy) or referral to an appropriate methadone or buprenorphine therapy 
program. 
Any subject that discontinues from the study, regardless of the reason, will be requested to 
complete all Study Discontinuation/End of Study assessments and procedures (see Table 1). 
The reason for discontinuation will be recorded on the end of study form provided in the 
subject’s eCRF.  Once discontinued, subjects may not re-enter the study.  Discontinued 
subjects will not be replaced. 
Study subjects discontinued from the protocol secondary to a medical or psychiatric concern 
deemed to be unrelated to lofexidine therapy will be referred, at the subject’s sole expense, 
for appropriate treatment, and may include psychological and lifestyle counseling, support 
groups, pharmacological, and medical treatment.  Subjects will be asked to sign a general 
consent for the release of information to the referred healthcare provider.  Study staff may 
request transportation for emergency treatment of a subject if medically appropriate (e.g., for 
acutely psychotic or suicidal subjects). 
14.5.2 Cardiovascular Events Requiring Subject Discontinuation From Study 
Subjects should be discontinued from the study for any of the reasons listed below, and the 
event should be recorded in the subject’s eCRF as an AE or SAE (see Sections 15.5.1, 16.7, 
and 16.8) and the subject followed until medically stabilized to the satisfaction of the study 
physician. 
1. New onset of clinically significant abnormal ECG per Investigator judgment 
(e.g., second or third degree heart block or uncontrolled arrhythmia, prolonged QTcF 
interval2). 
2. Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or 
fluids). 
3. Single occurrence of symptomatic bradycardia (as assessed by Principal 
Investigator/study physician/assigned staff, regardless of blood pressure) associated 
with chest pain, shortness of breath, or decreased level of consciousness. 
4. Persistent hypertension – resting blood pressure ≥185/110 mmHg recorded on 3 
separate occasions taken at least 5 minutes apart AND within a 1-hour time period.  If 
2 of 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. 
5. Medical Intervention for Cardiovascular Event:  Any medical intervention 
(nonmedication or medication inclusive) used for the treatment of any cardiovascular 
event, with the exception of a positional intervention in subjects displaying 
hypotension. 
                                                 
2 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 157


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 37 of 113 
6. Any other clinically significant cardiovascular signs or symptoms that would place the 
subject at risk. 
14.5.3 Trial Discontinuation 
The Sponsor (USWM) has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
• the incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects; 
• subject enrollment is unsatisfactory;  
• data recording is inaccurate or incomplete; and 
• the safety database is judged to be sufficient, i.e., a minimum of 300 subjects (across 
this protocol and earlier lofexidine clinical studies expected to meet FDA safety 
database requirements) have been treated with clinically relevant doses of lofexidine for 
a minimum of 7 days. 
14.6 Concomitant Therapy 
If the individual withdrawal treatment goal requires a specific concomitant medication 
(e.g., agonist-assisted total withdrawal, transition to buprenorphine or naltrexone, dose 
reduction of maintenance therapy), that concomitant medication is allowed.  At no time are 
clonidine, tricyclic antidepressants, and beta-receptor blockers allowed (see Section 12.8). 
Other concomitant medications or therapies are permitted throughout the study in either an 
in-clinic or outpatient setting, as clinically warranted.  The following medications were found 
to be useful in earlier lofexidine efficacy/safety studies and, for consistency, the Principal 
Investigator/study physician/assigned staff may consider their use in this study as 
appropriate. 
1. Guaifenesin (for cough). 
2. Alumina, Magnesia, and Simethicone (for emesis and nausea). 
3. Dioctyl sodium sulfosuccinate and psyllium hydrocolloid suspension (for constipation). 
4. Bismuth sulfate (Pepto-Bismol®) and loperamide (Imodium®) (for diarrhea). 
5. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (for headache, 
muscle aches, or other discomfort. 
6. Zolpidem, trazadone, and other benzodiazepines (for insomnia, depression, anxiety).   
The Principal Investigator/study physician/assigned staff should contact the Sponsor’s 
Medical Monitor regarding any questions on concomitant medications. 
The site should document in source any symptom that requires administration of any 
concomitant medication as an AE (see Section 15.5.1). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 158


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 38 of 113 
All medications taken will also be recorded in source and on the subject’s eCRF along with 
dose, dates of administration, and reason for use. 
15 CLINICAL EVALUATIONS 
A detailed Schedule of Study Assessments is provided in Table 1. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 159


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 39 of 113 
Table 1. 
Schedule of Study Assessments 
 
 
Screening 
 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
Activity 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
End of Study* 
Informed Consent Signed 
X 
 
 
 
 
 
Subject Number Assigned 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X (b) 
 
 
 
 
Prior Medication History 
Past 30 days 
X (b) 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and Smoking History 
X 
 
 
 
 
 
Mini-International Neuropsychiatric Interview  
X 
 
 
 
 
 
Infectious Disease Assessments (c) 
X 
 
 
 
 
 
Chest X-Ray (c) 
X 
 
 
 
 
 
Pregnancy Test (d) 
X 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
X 
Complete Physical Exam 
X 
X (b) 
X (e) 
As needed 
As needed 
X 
Admission to In-clinic Facility 
 
X (f) 
 
 
 
 
Study Medication Administration 
 
 
X (QID) 
X (QID) (t) 
Optional 
 
Medication Compliance 
 
 
X 
X 
X 
X 
Study Medication Taper 
 
 
 
 
X 
 
Discharge from In-clinic Facility 
 
 
 
Variable, but by Day 7 
 
 
Clinic Visit 
 
 
 
Daily if outpatient 
Daily 
 
Issue Subject Diary 
 
 
 
Daily if outpatient 
Daily 
 
12-Lead Electrocardiogram (duplicate) 
X (g) 
X (h) 
X (h) 
 
 
X (i) 
Urine Drug Screen (j) 
X 
X 
X 
X 
X 
X 
Vital Signs (Sitting/Recumbent & Standing BP 
and pulse; respiration; and temperature) 
X 
X 
X (k) 
X (k) (l) 
X (l) 
X 
Clinical Laboratory Tests (hematology, 
chemistry, urinalysis) 
X 
As needed 
As needed 
As needed 
As needed 
X 
Adverse Events Assessment 
 
 
X 
X 
X 
X 
C-SSRS Baseline Version 
 
X 
 
 
 
 
C-SSRS Since Last Visit Version 
 
 
X (n) 
X (n) 
X (n) 
X 
Short Opiate Withdrawal Scale of Gossop (o) 
 
X 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) (o) 
 
X 
X 
X 
X 
X 
Fingerprick Blood Sample 
 
 
X (p) 
X (q) 
X (p) (q) 
X (p) 
Concomitant Medications Assessment 
 
 
X 
X 
X 
X 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 160


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 40 of 113 
Table 1. 
Schedule of Study Assessments 
 
 
Screening 
 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
Activity 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
End of Study* 
Define Subject-Specific Withdrawal 
Treatment Goal 
X 
 
 
 
 
 
Assessment of Completion of Pre-defined 
Withdrawal Treatment Goal (r) 
 
 
X  
X 
X 
X 
Telephone Follow Up Contact 
 
 
 
 
 
X (s) 
Abbreviations:  BP = blood pressure, C-SSRS = Columbia Suicide Severity Scale, PK = pharmacokinetic, PPD = purified protein derivative, QID = 4 times daily 
* 
The study discontinuation/end of study assessments/procedures should always be done when subject exits from the study. 
(a) The Baseline period is the morning of admission, before dosing. 
(b) This form is to be updated at Baseline. 
(c) A chest x-ray is required only if a PPD skin test for tuberculosis is not done, the current PPD is positive, or if a past PPD was positive. 
(d) The urine sample collected on the first day of screening will be divided into two aliquots.  One sample will be sent to the central lab 
 for 
urinalysis and the other sample will be used for urine drug screening and immediate “dipstick” analysis of pregnancy (females only). 
(e) A complete physical exam will be done on Day 1 (3-4 hours after first dose) and as clinically warranted. 
(f) Subjects may be admitted to the hospital or clinic in the evening (Day -1) before study drug administration on Day 1. 
(g) Baseline 12-lead electrocardiograms (ECGs) will be done on one day during the screening period at 8 AM and 11:30 AM. 
(h) 12-lead ECGs (duplicate) before dosing on Day 1 at 8 AM and 3.5 hours (± 15 minutes) after dosing. 
(i) 12-lead ECGs (duplicate) before subject’s last dose and after dosing or, if applicable, at discontinuation from the study.  
(j) Urine drug screen will be done every day in an in-clinic setting to monitor for contraband and every day in an outpatient setting to monitor illicit drug use.  
(k) During in-clinic treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured before every 
dose and 3.5 hours after study medication administration at 8 AM, 1 PM, and 6 PM; respiration and temperature before 8 AM dose only. 
(l) During outpatient treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured at least once 
daily before dosing and 3.5 hours after dosing on Days 4-13 and once before any dose on Day 14 and at the End of Treatment/Study Discontinuation visit.  Oral temperature and 
respiration are not required measurements during outpatient treatment. 
(m) C-SSRS will be completed at 3.5 hours after the first dose (8 AM) on Days 1-3. 
(n) C-SSRS will be completed 3.5 hours after the first dose (8 AM) during in-clinic treatment or once daily before dosing during outpatient treatment. 
(o) During in-clinic treatment, effectiveness scales will be completed once daily:  the Short Opiate Withdrawal Scale of Gossop 3.5 hours (±10 minutes) after the first dose of study 
medication followed by COWS, and the assessment of completion of pre-defined withdrawal treatment goal.  Effectiveness scales will be completed daily before dosing during 
outpatient treatment. 
(p) A fingerprick blood sample for PK analysis will be collected concurrently with each scheduled ECG. 
(q) A fingerprick blood sample will be collected during outpatient treatment when the subject reports to the clinic each day (before next scheduled dose) for analysis of plasma 
lofexidine concentration to monitor compliance. 
(r) This form is to be completed by the Principal Investigator after completion of the SOWS-Gossop and COWS. 
(s) A follow-up telephone contact will be attempted 30 days after the subject’s last dose and will include an adverse event evaluation and an evaluation of the subject’s current 
treatment status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, buprenorphine, or naltrexone program). 
(t) Per Investigator judgment, subjects can be discharged from the study after receipt of at least one dose of study drug on Day 7 and after completion of all end-of-study procedures. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 161


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 41 of 113 
15.1 Screening Assessments 
Subjects seeking treatment for opioid dependence at one of the study sites will be screened 
for study enrollment.  Screening assessments must be completed within a 9-day time period.  
The screening visit will have a visit window of ±2 days.  Subjects will not be out of 
compliance if visit windows extend because of extraordinary events that make it impossible 
for subjects to complete a screening within the ±2-day window (e.g., holidays, vacations, 
personal emergencies).  Determination of the maximum visit window deviation is, however, 
at the discretion of the medical monitor.  Written informed consent must be obtained from all 
study subjects before initiation of any study procedures. 
The following screening assessments must be completed during screening after determining 
eligibility and written informed consent is obtained:  height; weight; vital signs 
(sitting/standing blood pressure and pulse; respiration; and temperature); blood collection for 
standard clinical safety laboratory assessments (including hematology and biochemistry); 
urine sample for confirmatory drug testing, urinalysis, and pregnancy assessment (if female); 
and infectious disease assessment (see Section 15.5.4.2) and a chest x-ray if a past PPD skin 
test for tuberculosis was positive. 
The urine sample collected will be divided into two aliquots:  one sample will go to the 
central lab 
 for urinalysis; the other sample will be used 
for “dipstick” analysis of pregnancy and qualitative drug screening. 
The assessments listed below must also be performed during screening. 
• 12-lead ECGs (in duplicate) will be done on one day during the screening period at 
8 AM and 11:30 AM. 
• Medical and smoking/alcohol history. 
• Complete physical examination. 
• Mini International Neuropsychiatric Interview (M.I.N.I.) [18, 19].  The M.I.N.I. will be 
performed once at screening only to (1) establish that each potential subject is opioid-
dependent (inclusion criterion #2) and (2) determine the absence of major psychiatric 
disorders (exclusion criterion #3). 
• Prior medications will be recorded to capture all medications taken in the past 30 days. 
• All opioids of abuse the subject has used will be recorded. 
In addition, each subject will have a short-term (within the 14-day study period) withdrawal 
treatment goal defined according the criteria below (see Appendix 4 for further details on this 
assessment). 
• Abrupt and total withdrawal (e.g., quitting heroin abruptly and totally), including 
whether naltrexone maintenance will be initiated as part of the short-term treatment 
goal. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 162


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 42 of 113 
• Agonist-assisted total withdrawal (e.g., quitting heroin with methadone or other 
agonist, including buprenorphine, given as needed to alleviate symptoms), including 
whether naltrexone maintenance will be initiated as part of the short-term treatment 
goal. 
• Step-down/dose reduction resulting in partial withdrawal (e.g., lowering methadone or 
buprenorphine maintenance dose or chronic pain medication dose). 
• Transition (e.g., transitioning from heroin or methadone to buprenorphine 
maintenance). 
15.2 Baseline Assessments 
The Baseline period is the morning of admission to the study, before dosing.  Prospective 
subjects who meet all eligibility criteria must be admitted to the study in time to give the first 
dose of study medication at 8 AM (±30 minutes). 
The assessments listed below will be performed during the Baseline period before dosing. 
• SOWS-Gossop. 
• COWS. 
• Vital signs (resting [sitting or recumbent, if applicable]) and standing blood pressure 
and pulse; respiration, temperature) measurements. 
• Repeat pregnancy assessment (by “dipstick”), if female. 
• Repeat urine drug screen (by “dipstick”). 
• Update Inclusion/Exclusion Criteria form to reflect Baseline assessments.  
• Update prior medication form to capture any new medications since screening. 
• Update complete physical exam form to capture any new physical findings since 
screening. 
• Columbia Suicide Severity Rating Scale (C-SSRS) (Baseline version; Appendix 5). 
• 12-lead ECGs (in duplicate) before the first dose on Day 1 at 8 AM. 
15.3 Assessments During Treatment 
15.3.1 Days 1-3 (Mandatory In-clinic) 
The assessments or procedures listed below will be performed daily (unless otherwise 
specified) on Days 1-3 (see Section 15.3.4 for assessments/procedures required for 
discontinuation from the study). 
• Study medication administration QID at 8 AM, 1 PM, 6 PM, and 11 PM. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 163


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 43 of 113 
• Effectiveness assessments at estimated time of maximum plasma concentration (Tmax, 
i.e., 3.5 hours after the first daily dose) including: 
 SOWS-Gossop; and 
 COWS. 
• Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
• Concomitant medication assessment. 
• Vital signs including blood pressure and pulse at rest (sitting [or recumbent if necessary 
because of an AE]) and standing (if able) before every dose and 3.5 hours after 
administration of study medication at 8 AM, 1 PM, and 6 PM (7 times per day); 
respiration and temperature before 8 AM dose only. 
• Continuous monitoring for AEs. 
• 12-lead ECGs (in duplicate) before the first dose on Day 1 at 8 AM and 3.5 hours 
(±15 minutes) after dosing.  
• A fingerprick blood sample for PK analysis will be collected concurrently with each 
scheduled ECG. 
• Clinical laboratory tests as clinically warranted. 
• Complete physical examination 3 to 4 hours after dosing on Day 1 and as clinically 
warranted. 
• C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours after the first dose (8 AM) 
on Days 1-3. 
• A qualitative urine drug screening (by on-site use of “dipsticks”) will be done every 
day to monitor for contraband. 
15.3.2 Days 4-7 (In-clinic/Outpatient) 
The assessments or procedures listed below will be performed daily (unless otherwise 
specified) on Days 4-7 (see Section 15.3.4 for assessments/procedures required for 
discontinuation from the study). 
• Study medication administration QID at 8 AM, 1 PM, 6 PM, and 11 PM. 
• SOWS-Gossop 3.5 hours after the first daily dose during in-clinic treatment; once daily 
before dosing during outpatient treatment. 
• COWS 3.5 hours after the first daily dose during in-clinic treatment; once daily before 
dosing during outpatient treatment. 
• Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 164


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 44 of 113 
• Concomitant medication assessment. 
• Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses if being treated as an outpatient. 
• Vital signs including blood pressure and pulse at rest (sitting [or recumbent if necessary 
because of an AE]) and standing (if able) during in-clinic treatment before every dose 
and 3.5 hours after administration of study medication at 8 AM, 1 PM, and 6 PM 
(7 times per day); respiration and temperature before 8 AM dose only. 
• Vital Signs including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able) at least once daily before dosing 
and 3.5 hours after dosing during outpatient treatment.  Note that if the subject cannot 
stay in the clinic for measurement of the 3.5-hour post-dose vital signs required on 
Days 4-7, they will be given a portable digital blood pressure machine for measurement 
of their vital signs at this required time point.  Subjects will also be provided a diary 
(Appendix 3) to record the measurements along with any symptoms of hypotension 
and/or bradycardia (see list in Section 13.2.2) the subject may have experienced. 
• A fingerprick blood sample will be collected during outpatient treatment when the 
subject reports to the clinic each day (before next scheduled dose) for analysis of 
plasma lofexidine concentration to monitor compliance. 
• AE assessment. 
• Clinical laboratory tests as clinically warranted. 
• Complete physical examination as clinically warranted. 
• C-SSRS (Since Last Visit Version; Appendix 6) at 3.5 hours after the first dose (8 AM) 
during in-clinic treatment; once daily before dosing during outpatient treatment. 
• Qualitative urine drug screening (by on-site use of “dipsticks”) will be done every day 
in an in-clinic setting to monitor for contraband and every day in an outpatient setting 
to monitor for illicit drug use. 
• Daily clinic visits and completion of subject diary for outpatients. 
Subjects not requiring extended lofexidine treatment can be discharged from the study on 
Day 7 after receipt of at least one dose of study drug and after all end-of-study procedures 
have been completed (see Section 15.3.4). 
15.3.3 Days 8-14 (Outpatient Only) 
Study medication is optional on Days 8-14 for subjects continuing to have withdrawal 
symptoms per the Principal Investigator’s judgment.  The assessments and procedures listed 
below will be performed daily (unless otherwise specified) (see Section 15.3.4 for 
assessments/procedures required for discontinuation from the study). 
• Daily clinic visits and completion of subject diary. 
• SOWS-Gossop before dosing. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 165


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 45 of 113 
• COWS before dosing. 
• Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
• Concomitant medication assessment. 
• Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses. 
• Vital Signs, including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able) at least once daily before dosing 
and 3.5 hours after dosing on Days 8-13 and once before any dose on Day 14.  Note 
that if subjects cannot stay in the clinic for measurement of the 3.5-hour post-dose vital 
signs required on Days 8-13, they will be given a portable digital blood pressure 
machine for measurement of their vital signs at this required time point.  Subjects will 
also be provided a diary (Appendix 3) to record the measurements along with any 
symptoms of hypotension and/or bradycardia (see list in Section 13.2.2) the subject 
may have experienced. 
• AE assessment. 
• Clinical laboratory tests as clinically warranted. 
• Complete physical examination as clinically warranted. 
• C-SSRS (Since Last Visit Version; Appendix 6) before dosing. 
• A fingerprick blood sample will be collected during outpatient treatment when the 
subject reports to the clinic each day (before next scheduled dose) for analysis of 
plasma lofexidine concentration to monitor compliance. 
• Qualitative urine drug screening (by on-site use of “dipsticks”) will be done every day 
in an outpatient setting to monitor for illicit drug use. 
15.3.4 Study Discontinuation/End of Study 
Any subject that discontinues from the study, regardless of the reason (see all scenarios listed 
in Section 14.5.1), will be requested to complete all Study Discontinuation/End of Study 
assessments and procedures as listed below after the last dose of study medication. 
• SOWS-Gossop. 
• COWS. 
• Completion of pre-defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Principal Investigator (after completion of 
the SOWS-Gossop and COWS). 
• Concomitant medication assessment. 
• Pill count and review of subject diary (Appendix 3) to measure compliance with 
previous day’s doses if not already performed. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 166


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 46 of 113 
• Vitals signs including blood pressure and pulse at rest (sitting [or recumbent if 
necessary because of an AE]) and standing (if able); respiration; and temperature.  
• AE assessment. 
• 12-lead ECGs (in duplicate) before the subject’s last dose and after dosing. 
• Clinical laboratory tests. 
• Complete physical examination (including body weight). 
• Pregnancy test. 
• Urine drug screen. 
• C-SSRS (Since Last Visit version; Appendix 6). 
15.3.5 30-Day Telephone Follow-up Contact 
A  follow-up telephone contact will be attempted 30 days after the subject’s last dose and 
will include an adverse event evaluation and an evaluation of the subject’s current treatment 
status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, 
buprenorphine or naltrexone program).  Repeated attempts will be made to reach the subject 
(defined as a minimum of 3 telephone calls, followed by sending a letter).  If repeated 
attempts are unsuccessful, this will be recorded in the subject’s source document and eCRF. 
15.4 Effectiveness Assessment Methods 
15.4.1 Assessment of Completion of Pre-Defined Withdrawal Treatment Goal 
The Principal Investigator will indicate if the subject has completed his/her pre-defined 
withdrawal treatment goal (Appendix 4) on Days 1-7 by responding to the following 
question:  “Has the subject’s withdrawal treatment goal been reached?”  Note that, per 
protocol, subjects are required to continue on their dose of lofexidine through Day 7 even 
though the subject may have completed his/her withdrawal treatment goal before Day 7.  
This same assessment will be made at each visit during the 7 days of optional outpatient 
treatment (Days 8-14).  This assessment should be completed after the SOWS-Gossop and 
COWS assessments. 
15.4.2 Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
The SOWS-Gossop [16] will be completed by the subject at baseline, once daily at 3.5 hours 
(± 10 minutes) after the first dose of study medication during in-clinic treatment and once 
daily before dosing during outpatient treatment.  Note that at the time of each daily 
evaluation, subjects should consider their symptoms over the last 24-hour period or since the 
last time the subject took this test.  Also, this scale should be completed before completion of 
the COWS. 
The SOWS-Gossop scale assesses subjective symptoms of opioid withdrawal (Appendix 1).  
It is a subject-rated scale consisting of 10 items that are scored on a 4-point scale of 0 = none, 
1 = mild, 2 = moderate, and 3 = severe (minimum score of 0, maximum score of 30) (see 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 167


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 47 of 113 
Table 2 below).  The overall score will be the simple sum of the 10-item scores.  Lower 
observed values in SOWS-Gossop scores indicate a more positive clinical outcome. 
Table 2. 
SOWS-Gossop Scoring Method 
Condition 
Score 
None 
Mild 
Moderate 
Severe 
Feeling Sick 
0 
1 
2 
3 
Stomach Cramps 
0 
1 
2 
3 
Muscle Spasms/Twitching 
0 
1 
2 
3 
Feeling of Coldness 
0 
1 
2 
3 
Heart Pounding 
0 
1 
2 
3 
Muscular Tension 
0 
1 
2 
3 
Aches and Pains 
0 
1 
2 
3 
Yawning 
0 
1 
2 
3 
Runny Eyes 
0 
1 
2 
3 
Insomnia/Problems Sleeping 
0 
1 
2 
3 
Note:  Possible score range = 0 to 30. 
 
15.4.3 Clinical Opiate Withdrawal Scale (COWS) 
The COWS [17] will be used to assess the effectiveness of lofexidine in alleviation of opioid 
withdrawal, and will be completed after the SOWS-Gossop and before the assessment of 
completion of pre-defined withdrawal treatment goal.  It will be completed during screening, 
at baseline (before dosing on Day 1), once daily at 3.5 hours after the first dose of study 
medication during in-clinic treatment, and once daily before dosing during outpatient 
treatment.  The COWS is a clinician-administered instrument that rates 11 common opioid 
withdrawal signs and symptoms (Appendix 2).  These include:  resting pulse rate; sweating; 
restlessness; pupil size; bone or joint aches; runny nose or tearing; gastrointestinal (GI) upset; 
tremor; yawning; anxiety or irritability; and gooseflesh skin.  The score for each item reflects 
the severity of the sign or symptom, and the total scores are grouped as mild (5-12 points), 
moderate (13-24 points), moderately severe (25-36 points), and severe (>36 points). 
15.5 Safety Assessment Methods 
15.5.1 Adverse Events 
The occurrence of AEs will be assessed starting at the treatment phase of the protocol 
(i.e., with the first dose of study drug).  Any AE that occurs during screening will be 
recorded in the subject’s Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
Adverse events will be assessed and recorded around the same time each day by study staff 
during in-clinic lofexidine treatment.  If an AE requires medical attention, it should be 
reported to a study physician immediately.  A study physician or assigned staff must meet 
with the subject to assess all medical and psychiatric AEs reported by the subject, as well as 
those recorded by other study 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 
physician or assigned staff must review with the subject and assess any AEs unresolved from 
the previous day.  For each daily AE assessment, details will be recorded in the subject’s 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 168


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 48 of 113 
source document and AE eCRF, according to the procedures described in Section 16.7, the 
type of AE and whether it is serious (SAE) or non-serious, severity of each AE, and the 
relationship to the study agent.  These categories are asking for the Principal Investigator or 
physician designee’s best judgment of the severity and relatedness of each AE.  The Principal 
Investigator or physician designee will also record, based on his/her best judgment, whether 
the AE is secondary to opioid withdrawal (see Section 15.5.1.1).  In general, an AE should 
not be marked as withdrawal related AND related to study medication. 
Any study subject with a related AE will be followed 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 be followed 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. 
During outpatient treatment, subjects will be queried about AEs at each daily clinic visit.  All 
subjects will be instructed to contact the study physician or assigned staff if he or she 
experiences any symptoms of hypotension and/or bradycardia (see list in Section 13.2.2) 
(especially on standing from a sitting or lying position) and delay additional lofexidine 
dosing until further instructed. 
All reported AEs will be recorded as described above. 
15.5.1.1 Withdrawal-Related Adverse Events 
The Principal Investigator or physician designee will also record, based on his/her best 
judgment, whether the AE is secondary to opioid withdrawal.  Individual items reported on 
the efficacy scales (i.e., SOWS-Gossop, COWS) do not automatically qualify as a 
withdrawal-related AE unless the subject specifically reports them in response to the non-
leading question (i.e., “How have you been feeling since I saw you last?”).  In the event a 
subject reports “withdrawal” or a similar event encompassing a collection of potential 
withdrawal symptoms, the subject should be asked to elaborate so that each specific 
symptom can be recorded on the AE eCRF.  In general, an AE/SAE should not be marked as 
withdrawal related AND related to study medication. 
15.5.2 Vital Signs 
Vital signs (sitting/standing systolic and diastolic blood pressure, pulse) will be measured at 
screening for all subjects. 
During in-clinic treatment (Days 1-3 mandatory; Days 4-7 if subject receives all lofexidine 
doses in the clinic), resting (sitting [or recumbent if necessary because of an AE]) and 
standing (if able) systolic and diastolic blood pressure and pulse will be measured within 
30 minutes before every dose and 3.5 hours (±15 minutes) after administration of study 
medication at 8 AM, 1 PM, and 6 PM; oral temperature and respiration before 8 AM dose 
only. 
During outpatient treatment (Days 4-14) resting (sitting [or recumbent if necessary because 
of an AE]) and standing (if able) systolic and diastolic blood pressure and pulse will be 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 169


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 49 of 113 
measured at least once daily before dosing and 3.5 hours (±30 minutes) after dosing on 
Days 4-13 and once before any dose on Day 14.  If the subject cannot stay in the clinic for 
measurement of the 3.5-hour post-dose vital signs required on Days 4-13, they will be given 
a portable digital blood pressure machine for measurement of their vital signs at this required 
time point and the values will be recorded in a subject diary (Appendix 3). 
For the orthostatic vital sign (i.e., blood pressure and pulse) readings, subjects will remain at 
rest for 3 minutes before a vital sign reading, and then stand for 3 minutes before a second 
vital sign reading is taken.  If a subject demonstrates potentially clinically significant vital 
signs (whether pre- or post-dose), as per the pre-defined criteria detailed in Sections 13.2.2 
and 13.2.3, the event should be recorded on the subject’s eCRF as an AE or SAE (see 
Sections 15.5.1, 16.7, and 16.8) and the subject should be followed until medically stabilized 
to the satisfaction of the study physician. 
Additionally, when the subject is experiencing blood pressure- or pulse-related symptoms 
(e.g., lightheaded, dizziness, palpitations), these should be recorded on the subject’s eCRF as 
an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) even if the vital signs values do not meet 
the pre-defined criteria detailed in Sections 13.2.2 and 13.2.3. 
15.5.3 12-Lead Electrocardiograms 
Using the ECG core lab-provided and validated instruments, baseline paper tracing 12-lead 
ECG (in duplicate) will be conducted on one day during the screening period at 8 AM and 
11:30 AM.  Duplicate 12-lead ECGs will also be conducted before the first dose on Day 1 at 
8 AM and 3.5 hours (±15 minutes) after dosing; before the subject’s last dose and after 
dosing; or, if applicable, at discontinuation from the study.  ECG intervals and abnormalities 
will be read centrally by a computer and confirmed by an individual accredited to read ECGs 
at the ECG core lab 
.  A qualified physician on site will evaluate tracings if there 
is a significant abnormality.  The following intervals will be computed: 
• Ventricular Rate 
Number of R waves appearing within a 6-second period, 
multiplied by 10; 
• PR Interval 
Measured from the onset of the P wave to the onset of the 
QRS complex; 
• QRS Complex 
Measured from the beginning of the down stroke of the 
Q wave to the completion of the upstroke of the S wave; 
• QT Interval 
Measured from the beginning of the down stroke of the 
Q wave to the completion of the T wave; 
• QTc (Bazett) 
QT interval corrected for heart rate using Bazett’s formula  
(QT/square root of RR); 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 170


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 50 of 113 
• QTc (Fridericia) 
QT interval corrected for heart rate using Fridericia’s  
formula (QT/cube root of RR) (for safety monitoring/subject 
discontinuation purposes). 
At screening (baseline assessment), a QTcF interval greater 
than 450 msec for males and greater than 470 msec for 
females will exclude the subject from study participation 
(see exclusion criterion #6 in Section 11.2.2).  In such cases, 
2 additional ECGs should be taken at 10- to 15-minute 
intervals.  The QTcF interval on all 3 ECGs should be 
confirmed by the Principal Investigator and if 2 of the 3 
QTcF intervals exceed the gender-specific cut-off, then the 
subject should be judged a screen failure. 
During the treatment phase of the study, when any QTcF 
interval exceeds 495 msec, 2 additional ECGs should be 
taken at 10- to 15-minute intervals.  The QTcF interval on 
all 3 ECGs should be confirmed by the Principal 
Investigator.  If it is determined that 2 of the 3 QTcF 
intervals exceed 500 msec or >25% above screen value, then 
the subject will be discontinued from the study. 
Any time that 2 of the 3 QTcF measurements exceed 
500 msec, contact the Sponsor’s Medical Safety Monitor, 
 
to discuss the subject and the 
AE/SAE determination. 
15.5.4 Clinical Laboratory Evaluations 
15.5.4.1 Standard Laboratory Tests 
Standard clinical laboratory safety evaluations (see Table 3) will be performed for all 
subjects at screening, as needed at the study physician’s discretion throughout the study, and 
at discontinuation from the study.  For this multicenter study, a central laboratory 
 
 will be used that is directly accredited by the College of 
American Pathologists (CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed every 2 years.  The 
laboratory will need to provide a copy of current certification and provide the normal values 
for all analytes to determine the upper limit of normal (ULN). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 171


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 51 of 113 
Table 3. Hematology, Chemistry, and Urinalysis Tests 
Hematology (a) 
Chemistry (b) 
Urinalysis 
Hemoglobin 
Cholesterol 
Color 
Hematocrit 
Triglycerides 
Clarity 
Red blood cell (RBC) count 
Sodium 
pH 
MCV 
Potassium 
Specific gravity 
MCH 
Chloride 
Protein 
MCHC 
Carbon dioxide (CO2) 
Glucose 
RDW 
Glucose 
Ketones 
White blood cell (WBC) count 
Creatinine 
Bilirubin 
WBC differential (% and Abs) 
Albumin 
Nitrite 
neutrophils 
Total protein 
Blood 
lymphocytes 
Calcium 
Urobilinogen 
monocytes 
Phosphorus 
WBC 
eosinophils 
Aspartate aminotransferase (AST) 
RBC 
basophils 
Alanine aminotransferase (ALT) 
Epithelial cells 
Prothrombin time (PT) 
Gamma-glutamyl transpeptidase  
Bacteria 
aPTT 
(GGTP) 
Casts 
Platelet Count 
Total bilirubin 
Crystals 
 
Lactate dehydrogenase (LDH) 
Leukocyte esterase 
 
Alkaline phosphatase 
 
 
Blood urea nitrogen (BUN) 
 
 
Thyroid-stimulating hormone (TSH) 
 
 
Free thyroxine (T4) 
 
Abbreviations:  Abs = absolute; aPTT = activated partial thromboplastin time; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; MCHC = mean corpuscular hemoglobin concentration; 
RDW = red blood cell distribution width 
(a) Blood will be collected in anticoagulant containing evacuated venous blood collection tubes 
(e.g., Vacutainer™). 
(b) Blood will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures. 
 
15.5.4.2 Infectious Disease Panel and Syphilis Tests 
The infectious disease panel and syphilis tests will be assayed as a baseline procedure.  Blood 
will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures.  Qualitative 
analysis reporting positive/negative results will be performed for the following analytes: 
Hepatitis B surface antigen (HbsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B core 
antibody (HBcAb), and Hepatitis C virus antibody (anti-HCV).  A PPD skin test for 
tuberculosis and/or a chest x-ray will be performed on all subjects.  If the PPD is positive, a 
chest x-ray is required to assess active tuberculosis.  If the subject reports that s/he has been 
previously positive for the PPD test, the PPD test will not be performed and only a chest 
x-ray will be required.  Syphilis antibody testing will be performed using an automated 
enzyme immunoassay (EIA).  If the EIA is positive, a confirmatory rapid plasma reagin 
(RPR) test will be performed.  If the RPR test is non-reactive, a confirmatory TPPA 
(treponema pallidum particle agglutination assay) test will be performed. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 172


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 52 of 113 
If the PPD with chest x-ray, chest x-ray, or RPR/confirmatory TPPA test is positive, subjects 
will not be eligible for study participation and will be referred, at subject’s sole expense, for 
appropriate follow-up and/or treatment. 
15.5.4.3 Urine Toxicology Screening 
A qualitative urine drug screen (UDS) will be performed at screening and Baseline (Day 1 
before dosing) for all subjects, and every day during in-clinic lofexidine treatment and 
outpatient lofexidine treatment for the following drugs:  amphetamines/ methamphetamines, 
cocaine, barbiturates, opiates, benzodiazepines, cannabinoids, methadone, and 
buprenorphine.  The central lab will provide standard sets of UDS “dipsticks” for use across 
all sites. 
15.5.4.4 Pregnancy Test 
A “dip-stick” pregnancy test designed to measure human chorionic gonadotropin will be 
performed on the first day of screening for all subjects, at Baseline (Day 1 before dosing), 
and at discontinuation from the study for all female subjects regardless of their childbearing 
capacity.  The central lab will provide study sites with a supply of pregnancy dipsticks. 
15.5.4.5 Pharmacokinetic Sampling 
A fingerprick blood sample will be collected concurrently with each scheduled ECG during 
the study. 
A fingerprick blood sample will be collected during outpatient treatment when the subject 
reports to the clinic each day (before next scheduled dose) for analysis of plasma lofexidine 
concentration to monitor compliance. 
15.5.5 Physical Examination 
A complete physical examination of the oral cavity, head, eyes, ears, nose and throat, 
cardiovascular system, lungs, abdomen (liver/spleen), extremities, skin, neuropsychiatric 
mental status and sensory/motor status, musculoskeletal system, and general appearance will 
be performed at screening for all subjects. 
An update of the Physical Exam is required at Baseline (before dosing on Day 1) and then a 
complete physical examination should be performed 3 to 4 hours after the first dose on 
Day 1, as clinically warranted throughout the study, and at discontinuation from the study. 
Height should be recorded at screening only. 
15.5.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS measures both suicidal ideation and suicidal behavior and will be completed at 
Baseline (before dosing on Day 1), 3.5 hours after the first dose (8 AM) during in-clinic 
lofexidine treatment, once daily before dosing during outpatient treatment or, if applicable, at 
discontinuation from the study.  The Baseline version of the C-SSRS (Appendix 5) will be 
used to assess lifetime suicidality on Day 1 (before dosing).  At all other protocol-specified 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 173


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 53 of 113 
time points, the C-SSRS – Since Last Visit version (Appendix 6) will be used to assess the 
subject’s suicidality since the last assessment. 
15.6 Other Assessments 
15.6.1 Prior Medications 
All medications taken by the subject for the 30 days before screening and during the 
screening period will be documented on the Prior Medication eCRF.  The reported 
medications will be reviewed and approved by the Principal Investigator/study 
physician/assigned staff for entry into the study. 
All opioids of abuse the subject has used will also be recorded at the screening visit. 
15.6.2 Concomitant Medication Administration 
Concomitant medication administration will be recorded daily.  All concomitant medications 
will be recorded in source and in the subject’s Concomitant Medication eCRF along with 
dose, dates of administration, and reason for use. 
16 REGULATORY AND REPORTING REQUIREMENTS 
16.1 Good Clinical Practices 
This study will be conducted in accordance with the most current version of the International 
Conference on Harmonization (ICH) Guideline for Good Clinical Practices (GCP).  An 
Investigational Site File binder will be provided to all investigational sites with additional 
instruction as well as a place to store regulatory and study documents.  The monitoring of the 
sites participating in the trial (either remote or on site) will be executed according to GCP 
guidelines and with a focused data review approach (Risk Based Monitoring [RBM]).  
Monitors will examine subjects’ study files including source documents in both the clinic 
files and subjects’ official medical records, and will also review regulatory/essential 
documents such as correspondence with the IRB and the Sponsor (USWM).  Areas of 
particular concern will be subject informed consent issues, protocol adherence, safety 
monitoring, IRB reviews and approvals, safety reports/regulatory forms, subject records, 
study drug accountability, and principal investigator supervision and involvement in the trial.  
Reports will be prepared following each visit and forwarded to the Sponsor’s Clinical Project 
Manager.  Monitors will also prepare follow-up letters detailing their findings and any items 
requiring further resolution or attention by the site.  Follow-up letters will be provided to the 
Principal Investigator, site coordinator, and Sponsor’s Clinical Project Manager. 
16.2 FDA Forms 1572 and Financial Disclosure 
The Principal Investigator will sign a Statement of Investigator (FDA Form 1572) before 
initiating this study.  The names of any sub-investigators must appear on this form. 
The Principal Investigator and sub-investigators will also sign Financial Disclosure forms 
before initiating this study. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 174


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 54 of 113 
16.3 Institutional Review Board Approval 
Before initiating the study, the Principal Investigator will obtain written IRB approval to 
conduct the study.  Study medication will not be shipped until IRB approval is obtained.  
Should changes to the study protocol become necessary, protocol amendments (provided by 
the Sponsor) will be submitted in writing to the central IRB and the Principal Investigator’s 
IRB for IRB approval before implementation.  In addition, IRBs will approve all advertising 
materials used for subject recruitment and any educational materials given to the subject.  
Annual reports and progress reports will be submitted to the IRB annually or at a frequency 
requested by the IRB. 
The IRB must be a properly constituted board or committee operating in accordance with 
GCP Title 21 Part 56 of the US CFR relating to IRBs and the ICH Guideline for GCP (E6). 
16.4 Informed Consent/HIPAA Authorization 
Properly executed written informed consent, in compliance with 21 CFR 50 and ICH 
guidelines, shall be obtained from each subject before entering the subject into the trial.  
Attention is directed to the basic elements that are required in the informed consent under 
US Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]).  Additional 
elements of informed consent, if appropriate, must be included in the informed consent 
document (21 CFR 50.25[b]).  A standard Informed Consent document will be approved by a 
central IRB.  Any study site that requires a site-specific Informed Consent document must 
have the document approved by the Sponsor before submission to the site’s IRB. The final 
IRB-approved document must be provided to the Sponsor for regulatory purposes. 
All potential subjects for the study will be given a current copy of the Informed Consent 
Form to read.  The Principal Investigator, sub-investigators, or study physician at each site 
will explain all aspects of the study in lay language and answer all of the subject’s questions 
regarding the study.  If the subject desires to participate in the study, s/he will be asked to 
sign the Informed Consent.  No subject will undergo any study procedures before signing the 
Informed Consent form, which should be signed before screening.  A signed copy will be 
given to the subject and a signed original shall be maintained in the subject’s clinical file as 
well as the Regulatory Binder at each study site.  Subjects who refuse to participate or who 
withdraw from the study will be treated without prejudice. 
Each subject must also sign a HIPAA (US Health Insurance Portability and Accountability 
Act) form before his/her participation in the study.  A signed copy must be provided to the 
subject and a signed original shall be maintained in the subject’s clinical file.  
16.5 Drug Accountability 
All study drug required for completion of this study will be provided by the Sponsor 
(USWM).  Upon receipt, the investigator/pharmacist is responsible for taking inventory of 
the investigational agents.  A record of this inventory must be kept and usage must be 
documented.  Any unused or expired investigational agent shall be returned to the Sponsor. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 175


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 55 of 113 
16.6 Outside Monitoring 
16.6.1 Medical Monitor 
The Sponsor’s (USWM) Medical Monitors,
 
will be responsible for attempting to establish concurrence with the Principal 
Investigator on the severity and seriousness of any AEs and SAEs, the relatedness to the 
study treatments, the expectedness of the event, and for determining if an SAE should be 
reported to the FDA in a 7- or 15-day expedited report or an annual report (Appendix 7).  
The Sponsor’s Medical Monitor will also be responsible for tracking and assessing trends in 
the SAEs reported.  Further, the Medical Monitor is available to consult with the Principal 
Investigators and coordinators on any medical issues related to the study (e.g., admission 
criteria, concomitant medications) and can be reached at 
 
and/or 
 
16.6.2 Clinical Monitors 
All Investigators will allow the Sponsor or its representatives to periodically audit, at 
mutually convenient times during and after the study, eCRFs and corresponding source 
documents as noted in the monitoring plan for each subject.  Using an RBM approach, 
monitoring may also occur remotely.  Monitoring both on site and via an RBM approach will 
provide an opportunity for evaluation of the progress of the study and to inform the Sponsor 
of potential problems. 
The study will be monitored according to an approved monitoring plan.  The monitors will 
assure that defined data outlined in the monitoring plan are accurate and in agreement with 
source documentation; verify that investigational agents are properly stored and accounted 
for; verify that subjects’ consent for study participation has been properly obtained and 
documented; confirm that research subjects entered into the study meet inclusion and 
exclusion criteria; and assure that all essential documentation required by GCP guidelines are 
appropriately filed. 
In lieu of an investigator meeting, USWM will host a web-based initiation meeting with 
study sites providing at a minimum protocol training, GCP training, CRF completion 
training, and a review of monitoring expectations.  For sites that did not participate in study 
USWM-LX1-3003-1, monitors will additionally conduct a site initiation visit before the start 
of the study.  At this visit, the monitor will assure that proper study-related documentation 
exists, assist in training investigators and other site personnel in study procedures and GCP 
guidelines, confirm receipt of study supplies, and assure that acceptable facilities are 
available to conduct the study. 
Periodic monitoring visits by USWM will be scheduled at appropriate intervals.  At the end 
of the study, they will advise on storage of study records and return of unused study agents.  
All sites should anticipate visits by the Sponsor, its representatives, and the FDA. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 176


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 56 of 113 
16.7 Adverse Event Reporting 
In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the Principal Investigator or sub-
investigators according to the specific instructions detailed in this section of the protocol and 
Appendix 7.  The occurrence of AEs will be assessed starting at the treatment phase of the 
protocol (i.e., with the first dose of study drug).  Any AE that occurs during screening will be 
recorded in the subject’s Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
An AE is defined as any reaction, side effect, or untoward event that occurs during the course 
of the clinical trial, whether or not the event is considered related to the investigational agent 
or clinically significant.  For this study, events reported by the subject, as well as clinically 
significant abnormal findings in the opinion of the Principal Investigator on physical 
examination, laboratory evaluation, or C-SSRS (for example, score of 3 or more on the scale) 
will be considered an AE and will be recorded on the AE eCRF.  A new illness, symptom, 
sign or clinically significant clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE.  Opioid withdrawal symptoms experienced by 
subjects during screening will be recorded on the Medical History eCRF and such symptoms 
will be recorded as AEs during the study even if they do not change or worsen.  Stable 
chronic conditions, such as arthritis, which are present before entry into the clinical trial and 
do not worsen are not considered AEs. 
For each daily AE assessment, details will be recorded in the subject’s source document and 
AE eCRF regarding the type of AE and whether serious (SAE) or non-serious, severity of 
each AE, and the relationship to the study agent.  These categories are asking for the 
Principal Investigator or physician designee’s best judgment of the severity and relatedness 
of each AE.  The Principal Investigator or physician designee will also record, based on 
his/her best judgment, whether the AE is secondary to opioid withdrawal.  In general, an AE 
should not be marked as withdrawal related AND related to study medication.  Also, if the 
sign or symptom is evaluated as part of the COWS assessment, it should generally be 
considered as withdrawal related and so marked if it is also reported as an AE. 
A study physician or assigned staff must review the AE eCRF for any events that are 
reported as beginning or as continuing.  All AEs, including clinically significant abnormal 
findings on laboratory evaluations, regardless of severity, will be followed by a study 
physician until satisfactory resolution. 
16.8 Serious Adverse Events (SAEs) 
Each adverse event or reaction will be classified by the Principal Investigator or physician 
designee as serious or non-serious.  Based on the seriousness of the adverse event or reaction, 
appropriate reporting procedures will be followed. 
The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH-E2A March 1995, as implemented by the US FDA, defines a serious adverse event 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 177


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 57 of 113 
(SAE) or serious adverse drug experience as any untoward medical occurrence at any dose 
that: 
• results in death during the period of protocol-defined surveillance; 
• 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.) 
• requires inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability or incapacity; or 
• results in a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life–threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, the 
event may jeopardize the subject and might require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
An unexpected event is one that is not described with respect to nature, severity, or frequency 
in the product package insert or Investigator’s Brochure. 
All subjects with SAEs must be followed up for outcome.  If a study subject withdraws from 
the study or if an investigator decides to discontinue the subject from the study because of a 
SAE, the subject must have appropriate follow-up medical monitoring including, if 
necessary, hospitalization. 
Reporting requirements for SAEs are described in detail in Appendix 7.  There can be serious 
consequences including ultimately, criminal and/or civil penalties for sponsors who fail to 
comply with FDA regulations governing the reporting of SAEs to the FDA.  Any SAEs, 
including death due to any cause, which occurs to any subject entered into treatment in this 
study or within 30 days following cessation of the last dose of treatment with the study 
medication, whether or not considered related to the investigational product, must be reported 
within 24 hours, from the time any study staff member is made aware of such, to the Sponsor 
(USWM). 
16.9 Pregnancy 
Although pregnancy is not considered an AE, it is the responsibility of the Principal 
Investigator or his/her designee to report any pregnancy in a subject (spontaneously reported 
to them or discovered during a protocol-defined pregnancy test) that occurs during the study 
or within 30 days of taking study medication.  All subjects who become pregnant must be 
withdrawn from the study and stop taking study medication.  The site must make appropriate 
effort (i.e., monthly calls) to follow the subject until completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of infant) must also be 
reported to the Sponsor.  If the subject cannot be reached after 3 telephone attempts, a 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 178


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 58 of 113 
certified letter should be sent.  Documentation of follow-up will be recorded in the source 
documents. 
17 STATISTICAL APPROACH 
17.1 General Considerations 
Continuous or ordered categorical variables not subject to censoring will be summarized with 
the mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and 
maximum.  Continuous or ordered categorical variables subject to censoring (e.g., time to 
removal from study treatment) will be summarized by the 25th percentile, median, 75th 
percentile derived from Kaplan-Meier estimates of probabilities.  Unordered categorical 
variables will be summarized with counts and percentages.  Descriptive statistics will be 
provided for the study population overall as well as by gender. 
Detailed methodology for the summary and statistical analyses of the data collected is this 
study will be documented in a Statistical Analysis Plan (SAP), which will be prepared and 
finalized before completion of the study. 
17.2 Assessment of Effectiveness 
Effectiveness measures will be summarized for the following subject cohorts: 
•
All exposed subjects;
•
Subjects undergoing abrupt and total withdrawal;
•
Subjects undergoing buprenorphine-assisted withdrawal;
•
Subjects transitioning to naltrexone maintenance;
•
Subjects transitioning to buprenorphine maintenance;
•
Subjects undergoing partial withdrawal to lower dose (e.g., chronic opioid medication
for pain); and
•
Any other identifiable cohorts not otherwise noted.
Descriptive statistics will be provided for: 
•
Demographics and baseline characteristics;
•
SOWS-Gossop;
•
COWS numerical score;
•
COWS severity category (i.e., mild, moderate, moderately severe, severe);
•
Number/proportion of subjects successfully completing their pre-defined withdrawal
treatment goal (e.g., planned detoxification/transition) as assessed by the Principal
Investigator;
•
Distribution of number of days required to complete withdrawal treatment goal by
category;
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 179


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 59 of 113 
• Concomitant medications; and 
• Evaluation of subject treatment status 30 days after last dose. 
17.3 Assessment of Safety 
Safety summaries will be provided for subjects who received lofexidine; any safety 
information on subjects who provide informed consent but do not receive lofexidine will be 
included in listings. 
Safety measures will be summarized for the following subject cohorts: 
• All exposed subjects; 
• Subjects undergoing abrupt and total withdrawal; 
• Subjects undergoing buprenorphine-assisted withdrawal; 
• Subjects transitioning to naltrexone maintenance;  
• Subjects transitioning to buprenorphine maintenance; 
• Subjects undergoing partial withdrawal to lower dose (e.g., chronic opioid medication 
for pain); and 
• Any other identifiable cohorts not otherwise noted. 
Descriptive statistics will be provided for: 
• AEs; 
• AEs of special interest, including orthostatic hypotension, orthostatic bradycardia, 
and syncope; 
• Vital signs; 
• ECGs;  
• Clinical laboratory tests; and 
• C-SSRS. 
18 DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) 
Data management activities, construction and accuracy of the study database, and statistical 
analytical support will be coordinated through USWM. 
18.1 Data Collection 
Data will be collected at the study sites on source documents, which will be entered at the 
site into electronic CRFs (eCRFs).  CRFs are to be completed on an ongoing basis during the 
study within 2 to 3 business days of a visit.  The medical chart and the source documents are 
the source of verification of data.  CRFs should be completed according to the instructions in 
the Investigational Site File binder. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 180


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 60 of 113 
The Principal Investigator is responsible for maintaining accurate, complete, and up-to-date 
records for each subject.  The Principal Investigator is also responsible for maintaining any 
source documentation related to the study, including any films, lab reports, or ECG tracings. 
Data generated by this study must be available for inspection by representatives of the 
US FDA, the Sponsor (USWM), the Sponsor’s representatives, the central IRB 
 or 
the site’s IRB. 
18.2 Electronic Data Capture 
Data entered by site personnel into the electronic data capture (EDC) system will be 
reviewed by the Sponsor or designee.  If incomplete or inaccurate data are found, a query in 
the EDC system will be generated for response by the clinical site.  Sites will promptly 
resolve data inconsistencies and errors.  An audit trail of any corrections or changes to the 
data in the EDC system will be maintained.  Feedback regarding CRF issues will be provided 
to all sites. 
The Principal Investigators agree to routine data audits by the staff of USWM or their 
designee.  USWM monitors will periodically visit each site to assure that data entered in the 
EDC system are in agreement with source documents at the sites per the monitoring plan.   
18.3 Data Analysis 
When the study is completed, all data have been entered into the clinical database, and the 
final database has been checked by Quality Assurance and then locked, statistical analysis of 
the data will be performed by USWM’s statisticians or an independent statistician in 
accordance with the Analytical Plan of this protocol (see Section 17) and detailed in the SAP.  
Periodically, during the investigation, USWM or designee will also prepare summary reports 
of the data so that progress of the study can be monitored. 
18.4 Study Documentation and Records Retention 
Study documentation includes all eCRFs, data correction forms, workbooks, source 
documents (paper or electronic), monitoring logs and appointment schedules, sponsor-
investigator correspondence and regulatory documents (e.g., signed protocol and 
amendments, IRB correspondence and approved consent form and signed informed consent 
forms, Statement of Investigator form, and clinical supplies receipt and distribution records). 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study.  Accordingly, source documents include, but are not limited to, laboratory reports, 
ECG tracings, x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound 
photographs, subject progress notes, hospital charts or pharmacy records, and any other 
similar reports or records of any procedure performed in accordance with the protocol.  
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.  Any duplicate of a source document to be retained as a 
part of an eCRF should maintain patient confidentiality per HIPAA. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 181


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 61 of 113 
Government agency regulations and directives require that the investigator must retain all 
study documentation pertaining to the conduct of a clinical trial.  These documents must be 
kept for a minimum of 2 years after the approval of a new drug application (NDA) and 
finalization of all marketing strategies, or if the NDA is not approved, for 2 years after 
discontinuation of the IND, whichever is the later.  In all instances, sites must get permission 
from USWM before disposition of any study documentation and materials. 
18.5 Confidentiality 
18.5.1 Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom 
of Information Act providing, in part, that proprietary information furnished to clinical 
investigators and IRBs will be kept confidential by the FDA only if maintained in confidence 
by the Principal Investigator and IRB. 
By participating in this protocol, the Principal Investigator affirms to USWM that 
information furnished to the Principal Investigator by USWM will be maintained in 
confidence and such information will be divulged to the IRB/Ethical Review Committee (or 
similar or expert committee), affiliated institution, and employees only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution, and 
employees. 
18.5.2 Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, CRFs (electronic or paper), 
reports, and other records will be coded using subject number and initials.  Only research 
staff and USWM staff or their designee will have access to the records.  Subject information 
will not be released without written permission, except as necessary for monitoring by the 
FDA or USWM.  USWM will file for a Certificate of Confidentiality that will cover all sites 
participating in the study (see Appendix 8). 
By participating in this protocol the investigator agrees that within local regulatory 
restrictions and ethical considerations, USWM or any regulatory agency may consult and/or 
copy study documents in order to verify eCRF data. 
Subject confidentiality will be maintained in any publications or presentations that result 
from this study. 
19 DISSEMINATION AND PUBLICATION OF STUDY RESULTS 
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages publication of such data in reputable scientific journals and at seminars or 
conferences.  The details of the processes of producing and reviewing reports, manuscripts, 
and presentations based on the data from this study is described in the Clinical Trial 
Agreement between the Sponsor and the institution of the Investigator. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 182


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 62 of 113 
20 PROTOCOL ADHERENCE AND AMENDMENTS 
The Principal Investigator and each sub-investigator must adhere to the protocol as detailed 
in this document.  Only the Sponsor (USWM) may modify the protocol.  All amendments 
that have an impact on subject risk or the study objectives, or require revision of the 
informed consent document, must receive approval from the central IRB/individual site’s 
IRB before their implementation. 
21 QUALITY CONTROL AND QUALITY ASSURANCE 
Following written standard operating procedures, study monitors will verify that the clinical 
trial is conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  Reports on monitoring activities will 
be submitted to the Sponsor. 
The Sponsor (USWM) will secure agreement from all involved parties to ensure direct access 
to all trial-related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by local and regulatory authorities. 
The Sponsor or designee will be the Data Coordinating Center and will implement quality 
control procedures in accordance with GCPs and their internal Standard Operating 
Procedures, beginning with the data entry system and generate data quality control checks 
that will be run on the database.  Any missing data or data anomalies will be communicated 
to the site for clarification and resolution. 
22 REFERENCES 
1. 
Substance Abuse and Mental Health Services Administration (SAMHSA), Office of 
Applied Studies (2008).  Results from the 2007 National Survey on Drug Use and 
Health:  National Findings (NSDUH Series H-34, DHHS Publication No.  SMA 
08-4343).  Rockville, MD.  http://oas.samhsa.gov 
2. 
National Institutes of Health.  Fact Sheet-Heroin Addiction.  September 2006.  
Bethesda, MD.  
http://www.nih.gov/about/researchresultsforthepublic/HeroinAddiction.pdf 
3. 
Archibold RC.  In heartland death, traces of heroin’s spread.  New York Times.  
May 30, 2009.  http://www.nytimes.com/2009/05/31/us/31border.html 
4. 
DAWN, Office of Applied Studies.  National Estimates of Drug-Related Emergency 
Department Visits, 2006. 
5. 
Methadone is a schedule II drug.  See 21 C.F.R. § 1308.12(c)(10) (isomethadone); 
§ 1308.12(c)(15) (methadone); and § 1308.12(c)(16) (methadone-intermediate, 
4-cyano-2-dimethylamino-4,4-diphenyl butane).  Buprenorphine is a schedule III drug.  
See 21 C.F.R. § 1308.13(e)(2)(i). 
6. 
Gowing L, Farrell M, Ali R, White JM.  Alpha 2-adrenergic agonists for the 
management of opioid withdrawal.  Cochrane Database Syst Rev 2008, Issue 4. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 183


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 63 of 113 
7. 
Kahn A, Mumford JP, Rogers GA, Beckford H.  Double-blind study of lofexidine and 
clonidine in the detoxification of opiate addicts in hospital.  Drug Alcohol Depend 
1997;44:57-61. 
8. 
Lin SK, Strang J, Su LW, Tsai CJ, Hu WH.  Double-blind randomized controlled trial 
of lofexidine versus clonidine in the treatment of heroin withdrawal.  Drug Alcohol 
Depend 1997;48:127-133. 
9. 
Carnwath T, Hardman J.  Randomised double-blind comparison of lofexidine and 
clonidine in the out-patient treatment of opiate withdrawal.  Drug Alcohol Depend 
1998;50:251-254. 
10. Gerra G, Zaimovica A, Giusti F, et al.  Lofexidine versus clonidine in rapid opiate 
detoxification.  J Subst Abuse Treatment 2001;21:11-17. 
11. Yu E, Herman BH, Miotto K, et al.  In-patient safety evaluation of lofexidine (alpha-2 
adrenergic agonist) for opiate detoxification.  Drug Alcohol Depend 2001;63: S175. 
12. Yu E, Miotto K, Akerele E, et al.  A phase 3 placebo-controlled, double blind, multi-
site trial of the α2-noradrenergic agonist, lofexidine, for opioid withdrawal.  Drug 
Alcohol Depend 2008;97:158-168. 
13. Gorodetzky CW.  A phase III, randomized, multi-center, double blind, placebo 
controlled study of safety and efficacy of lofexidine for relief of symptoms in subjects 
undergoing inpatient opiate detoxification.  US WorldMeds Report for Protocol 
USWM-LX1-3002, March 14, 2010. 
14. Heyman ER.  An open-label, single-dose, pilot study to determine the maximum 
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and 
women.  CardioCore Report 01496KM, April 27, 2010. 
15. Leibowitz MT.  An open-label, single-dose, pilot study to determine the maximum 
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and 
women.  CEDRA Report DCN 01496KM, April 22, 2010. 
16. Gossop M.  The development of a short opiate withdrawal scale (SOWS).  Addict 
Behav 1990;15(5):487-490. 
17. Wesson DR, Ling W.  The clinical opiate withdrawal scale (COWS).  J Psychoactive 
Drugs 2003;35(2):253-9. 
18. Medical Outcomes Systems.  M.I.N.I. International Neuropsychiatric Interview 
(M.I.N.I.), version 6.0 (10/10/10).  https://www.medical-outcomes.com/index/mini/.  
08 March 2013. 
19. Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al.  The M.I.N.I. International 
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured 
diagnostic psychiatric interview.  J Clin Psychiatry 1998;59(suppl 20):22-33. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 184


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 64 of 113 
23 PROTOCOL AMENDMENT DETAILS 
Table 4 lists changes made in Amendment No. 01 to the protocol for Study 
USWM-LX1-3003-2. 
 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 185


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 65 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Pages 1-53 
-- 
Pages 1-113 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
Global change to add SOWS-Gossop as an 
assessment, consistent with other lofexidine 
clinical trials. 
Pages 1-53 
-- 
Pages 1-113 
Columbia Suicide Severity Rating Scale (C-SSRS) 
Global change to add C-SSRS as a safety 
assessment, consistent with the current 
guidance to assess suicidality in all clinical 
studies involving central nervous system 
acting drugs. 
Pages 1-53 
Site Investigator 
Pages 1-113 
Principal Site Investigator 
Global change for protocol clarity. 
Pages 1-53 
Attending physician 
Pages 1-113 
Studyattending physician/  staff 
Global change to improve clarity of the 
protocol. 
Pages 1-53 
Case Report Form (CRF) 
Pages 1-113 
Case Report Form (CRF) 
Global change to remove reference to CRF 
as electronic CRFs will be used in the 
study. 
Pages 1-53 
CRO 
Pages 1-113 
CRO 
Global change to remove reference to CRO. 
Pages 1-53 
Number of subjects 200-400 
Pages 1-113 
Number of subjects 250-500200-400 
Global change based on the projected 
number of subjects completing 7 days of 
lofexidine treatment in the companion study 
(USWM-LX1-3003-1) and earlier 
lofexidine clinical programs expected to be 
appropriate for the FDA’s safety database 
requirements. 
Pages 1-53 
10 study sites 
Pages 1-113 
Approximately 2010 study sites 
Global change to allow additional sites to 
account for the potentially higher 
enrollment requirements and target study 
completion timelines 
Pages 1-53 
Structured Clinical Interview for DSM-IV-TR Axis I Disorders 
(SCID) 
Pages 1-113 
Mini International Neuropsychiatric Interview (M.I.N.I.)Structured 
Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) 
Global change for consistency with 
eligibility assessment in the companion 
study, USWM-LX1-3003-1. 
Pages 1-53 
Assessments at clinic visits every other day 
Pages 1-113 
Daily assessments including while inpatient and at daily clinic 
visits during outpatient treatmentClinic visits every other day 
Global change to more fully monitor the 
safety of lofexidine. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 186


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 66 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Pages 1-53 
-- 
Pages 1-113 
Subject Diary 
Global change to allow collection of vital 
signs data in an outpatient setting. 
Pages 1-53 
Pages 1-113 
Minor editorial changes made for 
consistency and to improve clarity of the 
protocol. 
Title Page, Page 1 
-- 
Title Page, Page 1 
Amendment No. 01 Date: 
January 22, 2015 
Administrative change. 
Title Page, Page 1 
Contract Research Organization   TBD 
Title Page, Page 1 
Contract Research Organization    TBD 
Administrative change. 
Header, Pages 2-53 
Protocol No. USWM-LX1-3003-2        February 3, 2012 
Header, Pages 2-113 
Protocol No. . USWM-LX1-3003-2, Amendment No. 01, 
January 22, 2015 
Administrative change. 
-- 
Section 2, Pages 3-5 
This section provides a summary of major changes made to the 
protocol for Study USWM-LX1-3003-2 in this current amendment 
(Amendment No. 01).  Section 23 provides a detailed accounting of 
all changes made in this amendment. 
[See protocol for summary/rationale of major changes.] 
Administrative change. 
Section 2, Page 3, Objective 
The primary objective is to investigate whether variable dose 
lofexidine treatment can be safely and effectively used along with 
usual standard of care in inpatient/outpatient detoxification from 
short-acting opioids in a variety of clinical situations in which the 
subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Section 3, Page 6, Objective 
To primary objective of this study is to continue to investigate the 
safety of lofexidine when administered for at least 7 days at 
clinically relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms 
of acute withdrawal from opioids in a variety of clinical scenarios 
in both in-clinic and outpatient settings.  The effectiveness is also of 
interest.The primary objective is to investigate whether variable 
dose lofexidine treatment can be safely and effectively used along 
with usual standard of care in inpatient/outpatient detoxification 
from short-acting opioids in a variety of clinical situations in which 
the subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 187


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 67 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 3, Study Design 
-- 
Section 3, Page 6, Study Design 
[Section extensively revised. See protocol for revisions.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 2, Page 3, Inclusion Criteria 
1. Be able to verbalize understanding of the consent form, able to 
provide written informed consent, verbalize willingness to 
complete study procedures, and pass the study consent quiz with 
100% accuracy (if necessary, quiz may be administered more 
than one time). 
Section 3, Page 6, Inclusion Criteria 
17. Be able to verbalize understanding of the consent form, able to 
provide written informed consent, and verbalize willingness to 
complete study procedures., and pass the study consent quiz 
with 100% accuracy (if necessary, quiz may be administered 
more than one time). 
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 2, Page 3, Inclusion Criteria 
3. Be seeking treatment for partial or total withdrawal from current 
opioid.  This can include a variety of clinical situations where 
opioid withdrawal illness is likely to occur.  Examples include 
abrupt and total withdrawal, agonist-assisted withdrawal (with 
the exception of methadone), transition to naltrexone or from 
buprenorphine, or decrease in dose (e.g., of chronic opioid 
medication for pain or of buprenorphine for opioid maintenance 
treatment). 
Section 3, Page 7, Inclusion Criteria 
43. Be seeking treatment for partial or total withdrawal from current 
opioid and expected, as determined by the Principal 
Investigator, to benefit from lofexidine treatment for at least 
7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This can 
include a variety of clinical situations where opioid withdrawal 
illness is likely to occur.  Examples include: 
• abrupt and total withdrawal (including from methadone and 
buprenorphine); 
• agonist-assisted total withdrawal (with the exception of 
methadone),; 
• dose reduction of maintenance treatment (e.g., of 
methadone or buprenorphine); and  
• transition from an opioid agonist to naltrexone or from 
buprenorphine maintenance., or decrease in dose (e.g., of 
chronic opioid medication for pain or of buprenorphine for 
opioid maintenance treatment). 
Revised to allow subjects with clinical 
treatment goals for full or partial 
withdrawal from methadone or 
buprenorphine. 
Section 2, Page 3, Inclusion Criteria 
4. Urine toxicology screen positive for opioids (including 
buprenorphine). 
Section 3, Page 7, Inclusion Criteria 
54. Urine toxicology screen positive for opioid(s) relevant to the 
subject’s withdrawal treatment goal (can includeing methadone 
and buprenorphine) at Screening. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 188


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 68 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 4, Inclusion Criteria 
6. Have completed the Clinical Opiate Withdrawal Scale (COWS)
during the Screening period.
Section 3, Page 7, Inclusion Criteria 
6. Have completed the Clinical Opiate Withdrawal Scale (COWS)
during the Screening period. 
Administrative change. 
Section 2, Page 4, Exclusion Criteria 
2. Be currently taking methadone, by self report or positive urine
drug screen.
Section 3, Page 7, Exclusion Criteria 
2. Be currently taking methadone, by self report or positive urine
drug screen. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 2, Page 4, Exclusion Criteria 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine
co administered with methadone is contraindicated.
Section 3, Page 7, Exclusion Criteria 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine
co administered with methadone is contraindicated. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 2, Page 4, Exclusion Criteria 
4.
Have a very serious medical illness not under control2; have
active self-reported acquired immune deficiency syndrome
(AIDS); or have an unstable psychiatric condition (e.g., suicide
risk).  It is the intent of the study to approach as closely as
feasible real-life conditions of treatment of opioid withdrawal.
Section 3, Pages 7-8, Exclusion Criteria 
24. Have a very serious medical illness not under control as
detailed below.
•
Serious medical illness will be determined at Screening by:
medical history;
physical examination;
12-lead electrocardiogram (duplicate);
clinical laboratory tests, including standard lab tests, an
infectious disease panel for syphilis (excluded if
positive), hepatitis (positive results do not exclude a
prospective subject from participation unless there is an
indication of active liver disease), and hepatitis
(positive results do not exclude a prospective subject
from participation unless there is an indication of active
liver disease); and
tuberculin test (purified protein derivative [PPD])
and/or a chest x-ray (a positive PPD result does not
exclude a prospective subject from participation, but if
diagnostic tests [e.g., chest x-ray] indicate that active
disease is present, the subject will be excluded from
participation).
•
Have active self-reported acquired immune deficiency
syndrome (AIDS) or self-reported human
immunodeficiency virus (HIV) positive status and taking
Revised for clarity and consistency with 
companion study, USWM-LX1-3003-1. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 189


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 69 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
retroviral medications currently or within the past 4 weeks. 
• Have an unstable psychiatric condition (e.g., suicide risk, 
per Investigator judgment). 
Have a very serious medical illness not under control2; have active 
self-reported acquired immune deficiency syndrome (AIDS); or 
have an unstable psychiatric condition (e.g., suicide risk).  It is the 
intent of the study to approach as closely as feasible real-life 
conditions of treatment of opioid withdrawal. 
Section 2, Page 4, Exclusion Criteria 
6. 
Have participated in an investigational drug study within the 
past 3 months. 
Section 3, Page 8, Exclusion Criteria 
4. Have participated in an investigational drug study within the 
past 30 days3 months. 
Revised for consistency with other 
protocols. 
-- 
Section 3, Page 8, Exclusion Criteria 
5. Have history of lofexidine exposure in a prior clinical trial or 
otherwise. 
Administrative change. 
Section 2, Page 5, Exclusion Criteria 
7. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
• clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTF interval greater than 450 msec for 
males and greater than 470 msec for females); 
• heart rate less than 55 bpm or symptomatic bradycardia; 
• systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
• diastolic blood pressure less than 65 mmHg; 
• blood pressure greater than 155/95 mmHg; and 
• prior history of myocardial infarction. 
Section 3, Page 8, Exclusion Criteria 
6. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
• clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTcF intervals greater than 450 msec for 
males and greater than 470 msec for females); 
• resting pulseheart rate less than 55 bpm or symptomatic 
bradycardia; 
• resting systolic blood pressure less than 95 mmHg or 
symptomatic hypotension; 
• resting diastolic blood pressure less than 65 mmHg; 
• resting blood pressure greater than 155/95 mmHg; and 
• prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the 
above criteria, the value should be confirmed by repeating the 
measurement (twice, if necessary).  If 2 of 3 values meet the above 
criteria, the subject will be excluded from participation. 
Administrative clarification/update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 190


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 70 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 3, Page 9, Exclusion Criteria 
7. 
To avoid drug-drug interactions, subjects requiring the 
following will be excluded: 
• tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and 
• beta-receptor blockers, to avoid the risk of excessive 
bradycardia. 
Added to improve clarity of the protocol. 
Section 2, Page 5 
N 
Total enrollment will depend on subject drop-out rates.  
Approximately 200 to 400 subjects will need to be enrolled 
and enrollment will remain open until a minimum total of 300 
subjects (among this protocol and companion Protocol USWM 
LX1 3003 1) have been treated with lofexidine for a minimum 
of 7 days. 
Section 3, Page 9 
N 
Total enrollment will depend on subject drop-out rates.  
Approximately 250200 to 500400 subjects: will need to be 
enrolled and enrollment will continueremain open until a 
minimum total of 300 subjects (across this protocol and earlier 
lofexidine clinical studies expected to meet FDA safety 
database requirements) (among this protocol and companion 
Protocol USWM LX1 3003 1) have been treated with 
clinically relevant doses of lofexidine for a minimum of 7 
days.  A target of at least 50 subjects each treated for clinical 
scenarios involving methadone or buprenorphine treatment 
will be enrolled (i.e., a total of 50 subjects receiving full or 
partial dose reduction from methadone, methadone-assisted 
withdrawal, and other methadone treatment scenarios and a 
total of 50 subjects receiving full or partial dose reduction 
from buprenorphine, transition to buprenorphine maintenance, 
and other buprenorphine treatment scenarios). 
Administrative update. 
-- 
Section 3, Page 9, Safety Endpoints 
• Occurrence, seriousness, severity, and causality assessment of 
adverse events. 
• Occurrence of adverse events of special interest (i.e., orthostatic 
hypotension, orthostatic bradycardia, syncope). 
• Occurrence of adverse events not related to opioid withdrawal. 
• Descriptive evaluation of vital signs (actual and change from 
baseline) for each time point. 
Added to align with study objectives. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 191


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 71 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
 
• Descriptive evaluation of the three C-SSRS subscales (suicidal 
ideation, suicidal behavior, and intensity of suicidal ideation). 
• Shifts from baseline in physical examination findings will be 
summarized. 
• Descriptive evaluation of clinical laboratory tests of hematology, 
chemistry, and urinalysis (actual and change from baseline). 
• Descriptive evaluation of ECG (actual and change from 
baseline). 
 
Section 2, Page 5, Endpoints 
• Number/proportion of subjects successfully completing planned 
detoxification/transition as assessed by the Site Investigator. 
• Descriptive evaluation of COWS numerical score, COWS 
severity score (i.e., mild, moderate, moderately severe, severe), 
duration of exposure; distribution of number of days required to 
complete detoxification, average daily dose of lofexidine, 
concomitant medications, and linkage to long term care (through 
subject treatment status report at the 30 day post dischargefollow-
up telephone contact). 
Section 3, Page 9, Effectiveness Endpoints 
• Number/proportion of subjects successfully completing their 
pre-defined withdrawal treatment goal (i.e., planned 
detoxification/transition) as assessed by the Principal Site 
Investigator. 
• Distribution of number of days required to complete withdrawal 
treatment goal by category. 
• Descriptive evaluation of SOWS-Gossop. 
• Descriptive evaluation of COWS numerical score and COWS 
severity score (i.e., mild, moderate, moderately severe, severe) 
• Concomitant medication analysis. 
• duration of exposure; distribution of number of days required to 
complete treatment goal by categorydetoxification, average daily 
dose of lofexidine, concomitant medications, and linkage to long 
term care (throughEvaluation of subject treatment status report 
at the 30 days after last dose.post discharge follow-up telephone 
contact). 
Revised to align with study objectives and 
improve clarity of the protocol. 
Section 2, Page 5, Duration 
21 days (maximum duration per subject, including screening) 
Section 3, Page 10, Duration 
2321 days (maximum duration per subject, including screening) 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 192


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 72 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 2, Page 5, Visits 
All subjects will undergo screening up to 7 days before study 
admission and will have clinic visits at least every other day for up 
to 14 days. 
Section 3, Page 10, Visits 
All subjects will undergo screening up to 97 days before study 
admission and will have clinic visits at least every other day for up 
to 14 days. 
Days 1-3 
• In-clinic setting:  Subjects may be admitted to clinic on Day -1 
Days 4-7 
• In-clinic setting OR daily visits for 4 days if outpatient 
Days 8-14 
• Daily outpatient visits for up 7 days 
Day30 
• Telephone follow-up contact 
Revised to require mandatory inpatient 
treatment for 3 days to allow more frequent 
safety monitoring during anticipated peak 
withdrawal and initiation of lofexidine 
therapy.  Also, option for inpatient/ 
outpatient treatment on Days 4-7 enables 
assessment, as clinically appropriate at the 
discretion of the Investigator, in a more 
flexible, real-world setting. 
Section 2, Page 5, Effectiveness Assessments 
Section 3, Pages 10-11, Safety Assessments 
[Section extensively revised.  See protocol for revisions.] 
Revised for consistency with study design 
changes. 
Section 2, Page 6, Safety Assessments 
Section 3, Page 11, Effectiveness Assessments 
[Section extensively revised.  See protocol for revisions.] 
Revised to align with study objectives and 
improve clarity of the protocol. 
Section 3, Pages 7-10 
Table of Contents, Appendices 
-- 
Section 4, Pages 12-15 
TOC updated to add the following appendices: 
Appendix 1 Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop) 
Appendix 2 Clinical Opiate Withdrawal Scale (COWS) 
Appendix 3 Subject Diary 
Appendix 4 Short-term Withdrawal Treatment Goal 
Appendix 5 Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline Version 
Appendix 6 Columbia Suicide Severity Rating Scale (C-SSRS) 
Since Last Visit Version 
Administrative change. 
Section 4, Pages 11-12 
-- 
Section 5, Pages 16-17 
[Abbreviation list updated.] 
Administrative change. 
Section 5.1, Pages 12-13 
-- 
Section 6.1, Page 18 
[Section extensively revised.  See protocol for revisions.] 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 193


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 73 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 5.3, Page 13, First Paragraph 
USWM has conducted 3 clinical trials (open-label tolerability and 
dose-response study and 2 randomized, double-blind, placebo-
controlled efficacy/safety studies) in support of the use of 
lofexidine in acute withdrawal from short-acting opioids. 
Section 6.3, Page 19, First Paragraph 
USWM has completedconducted 3 clinical trials (open-label 
tolerability and dose-response study and 2 randomized, double-
blind, placebo-controlled efficacy/safety studies) in support of the 
use of lofexidine in acute withdrawal from short-acting opioids.  In 
addition, USWM is currently conducting a randomized, double-
blind, placebo-controlled efficacy/safety study (USWM-LX1-3003-
1) of 2 doses of lofexidine (2.4 and 3.2 mg/day).
Administrative update. 
Section 5.4, Page 14, First Paragraph, 1st & 2nd Sentences 
A total of 2,032 subjects from clinical investigations of lofexidine 
(both USWM and externally sponsored) have been exposed to 
doses ranging from 0.1 mg to 4.0 mg total daily doses in a variety 
of dosing schedules from single doses to four times daily (QID) 
treatment over durations ranging from 1 day to 52 months (in the 
case of one antihypertension study).  In addition, an estimated 
214,000 documented BritLofex™ prescriptions have been sold in 
the UK where the standard dosing regimen prescribed is 2.4 mg 
total daily dose (0.8 mg three times daily or 0.6 mg QID) 
introduced on a dose escalation and maintained typically for 7 to 
10 days.   
Section 6.4, Page 20, First Paragraph, 1st & 2nd Sentences 
A total of 2,0442,032 subjects from clinical investigations of 
lofexidine (both USWM and externally sponsored) have been 
exposed to doses ranging from 0.1 mg to 4.0 mg total daily doses in 
a variety of dosing schedules from single doses to four times daily 
(QID) treatment over durations ranging from 1 day to 52 months (in 
the case of one antihypertension study).In addition, over 266,000 an 
estimated 214,000 documented BritLofex™ prescriptions have 
been sold in the UK (since product launch in 1992) where the 
standard dosing regimen prescribed is 2.4 mg total daily dose 
(0.8 mg three times daily or 0.6 mg QID) introduced on a dose 
escalation and maintained typically for 7 to 10 days.   
Administrative update. 
Section 5.5, Page 15 
-- 
Section 6.5, Page 21 
[Section extensively revised.  See protocol for revisions.] 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
Section 5.6, Page 16 
-- 
Section 6.6, Page 21 
[Section extensively revised.  See protocol for revisions.] 
Revised to add rationale for including 
SOWS-Gossop as an outcome measure. 
Section 6, Page 16 
The primary objective is to investigate whether variable dose 
lofexidine treatment can be safely and effectively used along with 
usual standard of care in inpatient/outpatient detoxification from 
short-acting opioids in a variety of clinical situations in which the 
subject is experiencing opioid withdrawal, excluding only co-
administration of methadone. 
Section 7, Page 22 
The primary objective is to continue to investigate the safety of 
lofexidine when administered for at least 7 days at clinically 
relevant doses (3.2 or 2.4 mg/day) to alleviate symptoms of acute 
withdrawal from opioids in a variety of clinical scenarios in both in-
clinic and outpatient settings.  The effectiveness of lofexidine is 
also of interest.The primary objective is to investigate whether 
variable dose lofexidine treatment can be safely and effectively 
used along with usual standard of care in inpatient/outpatient 
Revised based on study design change from 
variable dosing to standardized dosing (3.2 
or 2.4 mg/day for at least 7 days). 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 194


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 74 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
detoxification from short-acting opioids in a variety of clinical 
situations in which the subject is experiencing opioid withdrawal, 
excluding only co-administration of methadone. 
Section 9.1, Pages 16-17 
-- 
Section 10.1, Pages 22-23 
[Section extensively revised.  See protocol for revisions.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 9.2, Page 17 
The total enrollment in this study will depend on subject drop-out 
rates in this protocol and in companion study, Protocol USWM-
LX1-3003-1.  It is estimated that approximately 200 to 400 subjects 
will be enrolled in this open-label study in order to accrue a 
sufficiently large safety database for evaluation.  Enrollment will 
remain open until a minimum of 300 subjects (among this protocol 
and companion Protocol USWM-LX1-3003-1) complete a 
minimum of 7 days of treatment with lofexidine. 
Section 10.2, Page 23 
The total enrollment in this study will depend on subject drop-out 
rates in this protocol.  Enrollment will continue until a minimum 
total of 300 subjects (across this protocol and earlier lofexidine 
clinical studies expected to meet FDA safety database 
requirements) have been treated with clinically relevant doses of 
lofexidine for a minimum of 7 days. and in companion study, 
Protocol USWM-LX1-3003-1.  It is estimated that approximately 
250200 to 500400 subjects will be enrolled in this open-label study 
in order to accrue a sufficiently large safety database for 
evaluation.Enrollment will remain open until a minimum of 300 
subjects (among this protocol and companion Protocol USWM-
LX1-3003-1) complete a minimum of 7 days of treatment with 
lofexidine. 
Administrative update. 
Section 9.3, Page 17 
This study will be initiated after completion of the companion 
study, USWM-LX1-3003-1.  The maximum duration of 
participation for each subject in USWM-LX1-3003-2 will be 
21 days, including the Screening period, which can last up to 
7 days, followed by up to 14 days of flexible dose treatment with 
lofexidine.  
The study will be terminated when the database is judged to be 
sufficient, i.e., a minimum of 300 subjects, among this protocol and 
companion Protocol USWM-LX1-3003-1, completing at least 
7 days of treatment with lofexidine.  Enrollment is anticipated to 
take 5 to 10 months to achieve, with the total clinical duration of 
Section 10.3, Page 23 
This study will be initiated after completion of the companion 
study, USWM-LX1-3003-1.  The maximum duration of 
participation for each subject in USWM-LX1-3003-2 will be 
2321 days, including the Screening period, which can last up to 
97 days, followed by up to 14 days of flexible dose treatment 
with lofexidine.  
The study will be terminated when the database is judged to be 
sufficient, i.e., a minimum of 300 subjects (across this protocol and 
earlier lofexidine clinical studies expected to meet FDA safety 
database requirements) have been treated with clinically relevant 
doses of lofexidine for a minimum of 7 days.among this protocol 
Revised for consistency with study design 
changes and to improve clarity of the 
protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 195


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 75 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
USWM-LX1-3003-2 anticipated to be 8 to 12 months. 
and companion Protocol USWM-LX1-3003-1, completing at least 
7 days of treatment with lofexidine.  Enrollment is anticipated to 
take 45 to 10 months to achieve, with the total clinical duration of 
USWM-LX1-3003-2 anticipated to be 8 to 12 months. 
-- 
Section 10.4, Pages 23-24 
[Section added.  See protocol.] 
Added to improve clarity of the protocol. 
Section 10.1, Page 17, First Paragraph, First 3 Sentences 
Any opioid-dependent subject about to undergo complete or partial 
withdrawal from short-acting opioids or on buprenorphine 
maintenance treatment will be eligible for the study.  Entry into this 
study is open to both men and women and to all racial and ethnic 
subgroups.  An attempt will be made to include at least 25% female 
subjects and a mix of ethnicities reflecting the distribution in the 
local geographic regions of the study sites.  
Section 11.1, Page 24, First Paragraph, First 3 Sentences 
Any opioid-dependent subject about to undergo complete or partial 
opioid withdrawal and could benefit for a minimum of a 7-day 
treatment with lofexidine from short-acting opioids or on 
buprenorphine maintenance treatment will be eligible for the study. 
Entry into this study is open to both men and women and to all 
racial and ethnic subgroups.  An attempt will be made to include at 
least 25% female subjects, and a mix of ethnicities reflecting the 
distribution in the local geographic regions of the study sites, and a 
minimum of 50 subjects each on methadone or buprenorphine 
maintenance treatment.   
Revised for consistency with study design 
changes. 
Section 10.2.1, Page 19 
7. Be able to verbalize understanding of the consent form, able to
provide written informed consent, verbalize willingness to
complete study procedures, and pass the study consent quiz with
100% accuracy (if necessary, quiz may be administered more
than one time).
Section 11.2.1, Page 24 
17. Be able to verbalize understanding of the consent form, able to
provide written informed consent, and verbalize willingness to
complete study procedures., and pass the study consent quiz
with 100% accuracy (if necessary, quiz may be administered
more than one time). 
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 196


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 76 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.1, Page 18 
3. Be seeking treatment for partial or total withdrawal from current 
opioid.  This can include a variety of clinical situations where 
opioid withdrawal illness is likely to occur.  Examples include 
abrupt and total withdrawal, agonist-assisted withdrawal (with 
the exception of methadone), transition to naltrexone or from 
buprenorphine, or decrease in dose (e.g., of chronic opioid 
medication for pain or of buprenorphine for opioid maintenance 
treatment). 
Section 11.2.1, Page 25 
43. Be seeking treatment for partial or total withdrawal from 
current opioid and expected, as determined by the Principal 
Investigator, to benefit from lofexidine treatment for at least 
7 days at clinically relevant doses (3.2 or 2.4 mg/day).  This 
can include a variety of clinical situations where opioid 
withdrawal illness is likely to occur.  Examples include: 
• abrupt and total withdrawal (including from methadone and 
buprenorphine); 
• agonist-assisted total withdrawal (with the exception of 
methadone),; 
• dose reduction of maintenance treatment (e.g., of 
methadone or buprenorphine); and  
• transition from an opioid agonist to naltrexone or from 
buprenorphine maintenance., or decrease in dose (e.g., of 
chronic opioid medication for pain or of buprenorphine for 
opioid maintenance treatment). 
Revised to allow subjects with clinical 
treatment goals for full or partial 
withdrawal from methadone or 
buprenorphine. 
Section 10.2.1, Page 18 
4. Urine toxicology screen positive for opioids (including 
buprenorphine). 
Section 11.2.1, Page 25 
54. Urine toxicology screen positive for opioid(s) relevant to the 
subject’s withdrawal treatment goal (can includeing methadone 
and buprenorphine) at Screening. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 10.2.1, Page 18 
6. Have completed the COWS during the Screening period. 
Section 11.2.1, Page 25 
6. Have completed the COWS during the Screening period. 
Administrative change. 
Section 10.2.2, Page 19  
2. Be currently taking methadone, by self report or positive urine 
drug screen. 
Section 11.2.2, Page 25 
2. Be currently taking methadone, by self report or positive urine 
drug screen. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
Section 10.2.2, Page 19 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine 
co administered with methadone is contraindicated. 
Section 11.2.2, Page 25 
3. Seeking methadone-assisted withdrawal.  The use of lofexidine 
co administered with methadone is contraindicated. 
Revised for consistency with changes made 
in Inclusion Criterion #3. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 197


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 77 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.2, Page 19 
4.
Have a very serious medical illness not under control2; have
active self-reported acquired immune deficiency syndrome
(AIDS); or have an unstable psychiatric condition (e.g., suicide
risk).  It is the intent of the study to approach as closely as
feasible real-life conditions of treatment of opioid withdrawal.
Section 11.2.2, Pages 25-26 
24. Have a very serious medical illness not under control as
detailed below.
•
Serious medical illness will be determined at Screening by:
medical history;
physical examination;
12-lead electrocardiogram (duplicate);
clinical laboratory tests, including standard lab tests, an
infectious disease panel for syphilis (excluded if
positive), hepatitis (positive results do not exclude a
prospective subject from participation unless there is an
indication of active liver disease), and hepatitis
(positive results do not exclude a prospective subject
from participation unless there is an indication of active
liver disease); and
tuberculin test (purified protein derivative [PPD])
and/or a chest x-ray (a positive PPD result does not
exclude a prospective subject from participation, but if
diagnostic tests [e.g., chest x-ray] indicate that active
disease is present, the subject will be excluded from
participation).
•
Have active self-reported acquired immune deficiency
syndrome (AIDS) or self-reported human
immunodeficiency virus (HIV) positive status and taking
retroviral medications currently or within the past 4 weeks.
•
Have an unstable psychiatric condition (e.g., suicide risk,
per Investigator judgment).
Have a very serious medical illness not under control2; have active 
self-reported acquired immune deficiency syndrome (AIDS); or 
have an unstable psychiatric condition (e.g., suicide risk).  It is 
the intent of the study to approach as closely as feasible real-
life conditions of treatment of opioid withdrawal. 
Revised for clarity and consistency with 
companion study, USWM-LX1-3003-1. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 198


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 78 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.2.2, Page 19 
6. 
Have participated in an investigational drug study within the 
past 3 months. 
Section 11.2.2, Page 26 
46. Have participated in an investigational drug study within the 
past 30days3 months. 
Revised for consistency with other 
protocols. 
-- 
Section 11.2.2, Page 26 
5. Have history of lofexidine exposure in a prior clinical trial or 
otherwise. 
Administrative change. 
Section 10.2.2, Page 19 
7. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
• clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTF interval greater than 450 msec for 
males and greater than 470 msec for females); 
• heart rate less than 55 bpm or symptomatic bradycardia; 
• systolic blood pressure less than 95 mmHg or symptomatic 
hypotension; 
• diastolic blood pressure less than 65 mmHg; 
• blood pressure greater than 155/95 mmHg; and 
• prior history of myocardial infarction. 
Section 11.2.2, Page 26 
6. 
Abnormal cardiovascular exam at screening, including any of 
the following: 
• clinically significant abnormal electrocardiogram (ECG) 
(e.g., second or third degree heart block, uncontrolled 
arrhythmia, or QTcF intervals greater than 450 msec for 
males and greater than 470 msec for females); 
• resting pulseheart rate less than 55 bpm or symptomatic 
bradycardia; 
• resting systolic blood pressure less than 95 mmHg or 
symptomatic hypotension; 
• resting diastolic blood pressure less than 65 mmHg; 
• resting blood pressure greater than 155/95 mmHg; orand 
• prior history of myocardial infarction. 
Note: if a QTcF interval, blood pressure, or pulse value meets the 
above criteria, the value should be confirmed by repeating the 
measurement (twice, if necessary).  If 2 of 3 values meet the above 
criteria, the subject will be excluded from participation. 
Administrative clarification. 
-- 
Section 11.2.2, Page 26 
7. 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
• tricyclic antidepressants, which may reduce the efficacy of 
imidazoline derivatives; and  
• beta-receptor blockers, to avoid the risk of excessive 
bradycardia. 
Added to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 199


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 79 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 10.3, Page 20, First Full Paragraph 
Subjects who fail screening for any reason cannot be rescreened for 
study participation at a later time. 
Section 11.3, Page 26, Second Paragraph 
Subjects who fail screening for any reason cannot be rescreened for 
study participation at a later time. 
Administrative change. 
Section 11.2, Page 20, First Paragraph 
Lofexidine will be packaged and distributed through the pharmacy 
coordinating center (TBD).  Lofexidine tablets will be supplied in 
uniquely-identified 80-count bottles, which will be dispensed by the 
study pharmacist as determined clinically appropriate by the Site 
Investigator to the subject in individual prescription bottles.  The 
site will maintain a dispensing log for each bottle and document the 
number of tablets dispensed to each subject along with the number 
of tablets returned, if any, by the subject at each outpatient visit.  
Returned tablets will not be re-dispensed to future subjects. 
Section 12.2, Page 27, First Paragraph 
Lofexidine will be packaged and distributed through the pharmacy 
coordinating center (SharpTBD).  Lofexidine tablets will be 
supplied in uniquely-identified 80-count bottles.  During in-clinic 
treatment, lofexidine doses will be dispensed directly from the 
80-count bottles, whereas for outpatient treatment, doses which will 
be dispensed by the study pharmacist as determined clinically 
appropriate by the Site Principal Investigator or designee to the 
subject in individual prescription bottles.  One to 2 days of 
medication may be dispensed at each daily clinic visit to 
accommodate flexible scheduling (e.g., day and a half worth of 
medication to supply subject from one morning to the next 
afternoon depending on availability for clinic visit).  The site will 
maintain a dispensing log for each bottle and document the number 
of tablets dispensed to each subject along with the number of tablets 
returned, if any, by the subject at each outpatient visit.  Returned 
tablets will not be re-dispensed to future subjects. 
Administrative change/update. 
Section 11.4, Page 21 
Section 12.4, Page 28 
[Section extensively revised.  See protocol for revisions.] 
Administrative change. 
Section 11.5, Page 21 
The investigational agent, lofexidine, will be stored at room 
temperature in a secure location at the dispensing pharmacy. 
Section 12.5, Page 28 
The investigational agent, lofexidine, will be stored at room 
temperature in a secure location at the dispensing pharmacy.The 
investigational agent, lofexidine, will be stored at 68-77°F in a 
secure location at the dispensing pharmacy or site.  Temperature of 
the investigational agent will be maintained at 68-77°F during 
transport.  Temperature of the investigational agent will be 
monitored during storage and transport.  Temperature excursions 
will be reported to the Sponsor and the Sponsor will determine if 
the investigational agent is fit for use. 
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 200


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 80 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 12.6, Page 28, Second Sentence 
During outpatient treatment (Days 4-14), subjects are to record 
doses taken in his/her subject diary. 
Added to improve clarity of the protocol. 
Section 11.8, Pages 21-22 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
• 
tricyclic antidepressants – may reduce the efficacy of 
imidazoline derivatives; 
• 
alcohol, sedatives, and anesthetics – may interact with 
lofexidine and enhance its central sedative effects; and 
• 
beta-receptor blockers – the combination of lofexidine and 
beta-receptor blockers should be used with caution to avoid the 
risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug 
therapy and appropriate caution is warranted in subjects on such 
therapy.  The Principal Investigator may need to lower the subject’s 
antihypertensive dose during the study. 
Section 12.8, Page 29 
Clonidine is specifically prohibited in this study. 
To avoid drug-drug interactions, lofexidine should not be 
administered concurrently with: 
• 
tricyclic antidepressants – may reduce the efficacy of 
imidazoline derivatives; and 
• 
alcohol, sedatives, and anesthetics – may interact with 
lofexidine and enhance its central sedative effects; and 
• 
beta-receptor blockers – the combination of lofexidine and 
beta-receptor blockers should be used with caution to avoid the 
risk of excessive bradycardia. 
Lofexidine may enhance the effects of antihypertensive drug 
therapy and appropriate caution is warranted in subjects on such 
therapy.  The Principal Investigator may need to lower the subject’s 
antihypertensive dose during the study. 
Lofexidine should generally not be administered concurrently with 
alcohol, sedatives, and anesthetics as these may interact with 
lofexidine and enhance its central sedative effects. 
Revised to improve clarity of the protocol. 
Section 12.2.1, Page 22 
Section 13.2.1, Pages 29-30 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require in-clinic 
treatment for 3 days, either in-clinic or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 12.2.2, Page 23 
Section 13.2.2, Pages 30-31 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol. 
Section 12.2.3, Page23 
Section 13.2.3, Pages 31-32 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol. 
Section 12.3, Page 23 
Section 13.3, Pages 32-33 
[Section extensively revised.  See protocol for changes.] 
Revised for consistency with study design 
changes. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 201


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 81 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
-- 
Section 13.4, Page 33 
Section 13.4 Nicotine Replacement Therapy 
[Section added.  See protocol.] 
Added per study design change requiring 
in-clinic treatment for at least 3 days. 
Section 13.1, Page 24, First Paragraph, First Sentence 
Interested subjects, who respond to recruitment materials, will be 
scheduled to meet with a qualified investigative staff member and 
receive an explanation of the study purpose and requirements in lay 
language.   
Section 14.1, Page 33, First Paragraph, First Sentence 
Interested subjects, who respond to recruitment materials and are 
available to stay for the mandatory 3-day in-clinic treatment part of 
the study and available for participation in either an in-clinic or 
outpatient setting for 4 additional days (total commitment of 
7 days), will be scheduled to meet with a qualified investigative 
staff member and receive an explanation of the study purpose and 
requirements in lay language.   
Revised based on study design change 
requiring in-clinic treatment for at least 
3 days. 
Section 13.1, Page 24, Second Paragraph, First Sentence 
If still interested after receiving an explanation of the study, 
subjects will be given an opportunity to review, inquire about, and 
sign the study informed consent form (see Section 15.4).   
Section 14.1, Page 33, Second Paragraph, First Sentence 
If still interested after receiving an explanation of the study, a 
qualified investigative site staff member will review the study 
informed consent form with subjects, and subjects will be given an 
opportunity to review on their own, inquire about, and sign the 
study informed consent form (see Section 16.4).   
Administrative clarification. 
Section 13.1, Page 24, Second Paragraph, 4th & 5th Sentences 
Screening assessments must be completed within a 7-day time 
period, but can be completed as early as screening day 1.  At no 
time during the screening process should individuals be given 
information regarding inclusion or exclusion criteria, with the 
exception that subjects will be informed that they must exhibit signs 
of opioid withdrawal immediately before admission into the study. 
Section 14.1, Page 33, Second Paragraph, 4th & 5th Sentences 
Screening assessments must be completed within a 97-day time 
period, but can be completed as early as the first screening day 1.  
At no time during the screening process should individuals be given 
information regarding inclusion or exclusion criteria, with the 
exception that subjects will be informed that they must exhibit signs 
of opioid withdrawal immediately before admission into the study. 
Administrative clarification. 
Section 13.1, Page 24, Third Paragraph, Second Sentence 
Subjects must complete a consent quiz with 100% accuracy.   
Section 14.1, Page 33, Third Paragraph, Second Sentence 
Subjects must complete a consent quiz with 100% accuracy.   
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 13.1, Page 24, Last Paragraph, Second Sentence 
Subjects who are excluded, or who decline participation, may not 
be rescreened at a later time and will be given referrals to other 
resources in the area. 
Section 14.1, Pages 33-34, Last Paragraph, Second Sentence 
Subjects who are excluded, or who decline participation, may not 
be rescreened at a later time, although at least 30 days must occur 
between screeningsand will be given referrals to other resources in 
the area. 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 202


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 82 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 13.3, Pages 24-25 
Section 14.3, Page 34 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require in-clinic 
treatment for 3 days, either in-clinic or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 13.4, Page 25 
Section 14.4, Page 35 
[Section extensively revised.  See protocol for changes.] 
Administrative update. 
Section 13.5.1, Page 25, Numbered Items 
-- 
Section 14.5.1, Page 35, Numbered Items 
2. Abnormal vital signs or ECG meeting criteria in Section 13.2.3. 
Administrative clarification. 
Section 13.5.1, Page 25, Numbered Items 
4. Evidence of illicit drug use while participating in the study. 
5. Alcohol or other sedative/hypnotic withdrawal signs and 
symptoms developing following enrollment into the study. 
Section 14.5.1, Page 35, Numbered Items 
4. 
Evidence of illicit drug use while participating in the study. 
5. 
Alcohol or other sedative/hypnotic withdrawal signs and 
symptoms developing following enrollment into the study 
(Days 1-3). 
Administrative clarification. 
Section 13.5.2, Page 26, Numbered Items 
1. New onset of clinically significant abnormal ECG (e.g., second 
or third degree heart block or uncontrolled arrhythmia, 
prolonged QTc interval5). 
2. Persistent symptomatic hypotension (e.g., hypotension not 
responding to bed rest). 
4. Persistent hypertension – blood pressure ≥185/110 mmHg 
recorded on 3 separate occasions taken at least 5 minutes apart 
AND within a 1-hour time period.  If all 3 readings are 
≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be terminated. 
Section 14.5.2, Page 36, Numbered Items 
1. New onset of clinically significant abnormal ECG per 
Investigator judgment (e.g., second or third degree heart block or 
uncontrolled arrhythmia, prolonged QTcF interval5). 
2. Persistent symptomatic hypotension (e.g., hypotension not 
responding to bed rest or fluids). 
4. Persistent hypertension – resting blood pressure ≥185/110 
mmHg recorded on 3 separate occasions taken at least 5 minutes 
apart AND within a 1-hour time period.  If all 2 of 3 readings are 
≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. terminated 
Administrative clarification. 
Section 13.5.3, Page 27 
-- 
Section 14.5.3, Page 37, Last Bullet 
• the safety database is judged to be sufficient, i.e., a minimum of 
300 subjects (across this protocol and earlier lofexidine clinical 
studies expected to meet FDA safety database requirements) 
have been treated with clinically relevant doses of lofexidine for 
a minimum of 7 days. 
Administrative update. 
Section 13.6, Page 27 
Section 14.6, Page 37 
[Section extensively revised.  See protocol for changes.] 
Revised to improve clarity of the protocol 
and to relax requirements for concomitant 
therapy. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 203


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 83 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14, Page28, Table 1 
Section 15, Pages 39-40, Table 1 
[Table 1 extensively revised.  See protocol for changes.] 
Revised for consistency with study design 
changes. 
Section 14.1, Page 29 
Section 15.1, Pages 41-42 
[Section extensively revised.  See protocol for changes.] 
Administrative update and revised for 
consistency with study design changes. 
-- 
Section 15.2, Page 42 
Section 15.2  Baseline Assessments 
[Section added.  See protocol for changes.] 
Added based on study design changes. 
Section 14.2, Pages 29-30 
Section 15.3, Pages 42-46 
Section extensively revised, including the following subheadings: 
15.3.1  Days 1-3 (Mandatory In-clinic) 
15.3.2  Days 4-7 (In-clinic/Outpatient) 
15.3.3  Days 8-14 (Outpatient Only) 
15.3.4  Study Discontinuation/End of Study 
15.3.5  30-Day Telephone Follow-up Contact 
[See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Section 14.3.1, Page 30 
At each visit, the Site Investigator will indicate if the subject has 
completed the planned withdrawal or transition and can be 
discharged without further lofexidine treatment. 
Section 15.4.1, Page 46 
15.4.1  Assessment of Completion of Pre-Defined Withdrawal 
Treatment GoalPlanned Detoxification/Transition 
At each visit, The Site Principal Investigator will indicate if the 
subject has completedthe planned withdrawal or transition and can 
be discharged without further lofexidine treatment.his/her pre-
defined withdrawal treatment goal (Appendix 4) on Days 1-7 by 
responding the following question:  “Has the subject’s withdrawal 
treatment goal been reached?”  Note that, per protocol, subjects are 
required to continue on their dose of lofexidine through Day 7 even 
though the subject may have competed his/her withdrawal 
treatment goal before Day 7.  This same assessment will be made at 
each visit during the 7 days of optional outpatient treatment 
(Days 8-14).  This assessment should be completed after the 
SOWS-Gossop and COWS assessments. 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
-- 
Section 15.4.2, Pages 46-47 
15.4.2  Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop 
[Section added.  See protocol.] 
Added as an assessment, consistent with 
other lofexidine clinical trials. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 204


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 84 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.3.2, Page 30, First Sentence 
The COWS will be used to assess the effectiveness of lofexidine in 
alleviation of opioid withdrawal (at least every other day before 
dosing). 
Section 15.4.3, Page 47, First and Second Sentences 
The COWS [17] will be used to assess the effectiveness of 
lofexidine in alleviation of opioid withdrawal(at least every other 
day before dosing), and will be completed after the SOWS-Gossop 
and before the assessment of completion of pre-defined withdrawal 
treatment goal.  It will be completed during screening, at baseline 
(before dosing on Day 1), once daily at 3.5 hours after the first dose 
of study medication during inpatient treatment, and once daily 
before dosing during outpatient treatment. 
Administrative clarification. 
Section 14.4.1, Page 31, First Paragraph 
-- 
Section 15.5.1, Page 47, First Paragraph 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol (i.e., with the first dose of study drug).  Any 
AE that occurs during screening will be recorded in the subject’s 
Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
Administrative clarification. 
Section 14.4.1, Page 31, First Paragraph, First Sentence 
Subjects will be queried about adverse events at least every other 
day by study staff.  If an AE requires medical attention, it should be 
reported to a study physician immediately.   
Section 15.5.1, Page 47, Second Paragraph, First Sentence 
Adverse events will be assessed and recorded around the same time 
each day by study staff during in-clinic lofexidine 
treatment.Subjects will be queried about adverse events at least 
every other day by study staff.. 
Added based on study design change 
requiring in-clinic treatment. 
Section 14.4.1, Page 31, First Paragraph, 5th and 6th Sentences 
After each AE assessment, the physician will record on the AE 
eCRF, according to the procedures described in Section 15.7, the 
type of AE and whether serious (SAE) or non-serious, severity of 
each AE, and the relationship to the study agent.  These categories 
are asking for the physician’s best judgment of the severity and 
relatedness of each AE.  The physician will also record, based on 
his/her best judgment, whether the AE is secondary to opioid 
withdrawal.   
Section 15.5.1, Pages 47-48, Second Paragraph, 6th, 7th & 8th 
Sentences 
ForAfter each daily AE assessment, the physician details will be 
recorded in the subject’s source document and on the AE eCRF, 
according to the procedures described in Section 16.7, the type of 
AE and whether serious (SAE) or non-serious, severity of each AE, 
and the relationship to the study agent.  These categories are asking 
for the Principal Investigator or physician designee’s best judgment 
of the severity and relatedness of each AE.  The Principal 
Investigator or physician designee will also record, based on his/her 
best judgment, whether the AE is secondary to opioid withdrawal 
(see Section 15.5.1.1).  
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 205


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 85 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.1, Page 31, Third Paragraph 
All subjects will be instructed to contact the treating physician if he 
or she feels dizzy (especially on standing from a sitting or lying 
position) and delay additional lofexidine dosing until instructed by 
the physician. 
Section 15.5.1, Page 48, Fourth and Fifth Paragraphs 
During outpatient treatment, subjects will be queried about AEs at 
each daily clinic visit.  All subjects will be instructed to contact the 
studytreating physician or assigned staff if he or she experiences 
any symptoms of hypotension and/or bradycardia (see list in 
Section 13.2.2) feels dizzy (especially on standing from a sitting or 
lying position) and delay additional lofexidine dosing until further 
instructed by the physician. 
All reported AEs will be recorded as described above. 
Revised for consistency with study design 
changes. 
-- 
Section 15.5.1.1, Page 48 
15.5.1.1  Withdrawal-Related Adverse Events 
[Section added.  See protocol.] 
Revised for consistency with companion 
study USWM-LX1-3003-1. 
Section 14.4.2, Pages 31-32 
Section 15.5.2, Pages 48-49 
[Section extensively revised.  See protocol for changes.] 
Revised based on study design change to 
not allow flexible dosing, require inpatient 
treatment for 3 days, either inpatient or 
outpatient treatment for 4 days, and allow 
optional 7 days of outpatient treatment. 
Also, potentially clinically significant vital 
signs were clarified to improve clarity of the 
protocol. 
Section 14.4.3, Pages 32-33, First Paragraph 
Using ECG core lab-provided and validated instruments, baseline 
paper tracing 12-lead ECG (in duplicate) will be conducted on one 
day during the screening period at 8 AM and 11:30 AM.  Duplicate 
12-lead ECGs will also be conducted before the first daily dose and
3.5 hours after the first daily dose on Days 1 and 14 or, if
applicable, early discharge/termination from the study.  ECG
intervals and abnormalities will be read centrally by a computer and
confirmed by an individual accredited to read ECGs at the ECG
core lab (TBD).  A cardiologist on site will evaluate tracings if
there is significant abnormality.  The following intervals will be
computed:
Section 15.5.3, Page 49, First Paragraph 
Using the ECG core lab-provided and validated instruments, 
baseline paper tracing 12-lead ECG (in duplicate) will be conducted 
on one day during the screening period at 8 AM and 11:30 AM.  
Duplicate 12-lead ECGs will also be conducted before the first 
daily dose on Day 1 at 8 AM and 3.5 hours (± 15 minutes) after 
dosing; before subject’s last dose and after dosing;the first daily 
dose on Days 1 and 14 or, if applicable, early 
discharge/terminationat discontinuation from the study.  ECG 
intervals and abnormalities will be read centrally by a computer and 
confirmed by an individual accredited to read ECGs at the ECG 
core lab 
A qualified physiciancardiologist on 
site will evaluate tracings if there is a significant abnormality.  The 
following intervals will be computed: 
Administrative update and revised to 
improved clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 206


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 86 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.3, Pages 32-33, Bulleted List 
-- 
Section 15.5.3, Page 50, Bulleted List 
• 
QTc (Fridericia) 
QT interval corrected for 
heart rate using Fridericia’s formula 
(QT/cube root of RR) (for safety 
monitoring/subject discontinuation 
purposes). 
Added for consistency with companion 
study USWM-LX1-3003-1. 
Section 14.4.3, Page 33, Last Paragraph 
Any time that 2 of the 3 QTc measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor,
 
 to discuss the subject and the 
AE/SAE determination. 
Section 15.5.3, Page 50, Last Paragraph 
Any time that 2 of the 3 QTcF measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor,
 
 
to discuss the subject and the AE/SAE determination. 
Administrative update to add 
 
as back up Medical Monitor. 
Section 14.4.4.1, Page 33, First Paragraph 
Standard clinical laboratory safety evaluations (see Table 2) will be 
performed for all subjects at screening, as needed at the physician’s 
discretion throughout the study, and on Day 14 or, if applicable, 
early discharge/termination from the study.  For this multicenter 
study, a central laboratory will be identified by the Sponsor which 
is directly accredited by the College of American Pathologists 
(CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed 
every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the normal values for all analytes 
to determine the upper limit of normal (ULN). 
Section 15.5.4.1, Page 50, First Paragraph 
Standard clinical laboratory safety evaluations (see Table 3) will be 
performed for all subjects at screening, as needed at the study 
physician’s discretion throughout the study, and on Day 14 or, if 
applicable, early discharge/termination at discontinuation from the 
study.  For this multicenter study, a central laboratory
 
will be identified by the Sponsor which used 
that is directly accredited by the College of American Pathologists 
(CAP) and licensed by the Clinical Laboratory Improvement Act of 
1988 (CLIA); both certification and accreditation must be renewed 
every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the normal values for all analytes 
to determine the upper limit of normal (ULN). 
Administrative clarification/update. 
Section 14.4.4.1, Page 34, Table 2 
Section 15.5.4.1, Page 51, Table 3 
[Table 3 updated.  See protocol.] 
Table 3 was updated for consistency with 
the laboratory tests routinely conducted by 
the central laboratory. 
Section 14.4.4.2, Page 34, First Paragraph, Seventh Sentence 
A rapid plasma reagin (RPR) test for syphilis will be performed.  If 
positive, a confirmatory test (FTA-ABS or MHA-TP) will be 
performed. 
Section 15.5.4.2, Page 51, First Paragraph, Seventh Sentence 
A rapid plasma reagin (RPR) test for sSyphilis antibody testing will 
be performed using an automated enzyme immunoassay (EIA).  If 
the EIA is positive, a confirmatory rapid plasma reagin (RPR) test 
(FTA-ABS or MHA-TP) will be performed.  If the RPR test is non-
reactive, a confirmatory TPPA (treponema pallidum particle 
agglutination assay) will be performed. 
Revised for consistency with tests used by 
the central laboratory. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 207


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 87 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.4.2, Page 34, Second Paragraph 
If either PPD with chest x-ray, chest x-ray, or the confirmatory test 
for RPR is positive, subjects will not be eligible for study 
participation and will be referred, at subject’s sole expense, for 
appropriate follow-up and/or treatment. 
Section 15.5.4.2, Page 52, Second Paragraph 
If either the PPD with chest x-ray, chest x-ray, or the confirmatory 
test for RPR/confirmatory TPPA test is positive, subjects will not 
be eligible for study participation and will be referred, at subject’s 
sole expense, for appropriate follow-up and/or treatment. 
Revised for consistency with tests used by 
the central laboratory. 
Section 14.4.4.3, Page 35 
Qualitative urine drug screening will be performed at screening for 
all subjects and at least every other day during lofexidine treatment. 
Urine will be sent to a central laboratory for qualitative analysis for 
drugs of abuse.  The methodology will detect specific drugs or 
metabolites in the urine. 
Section 15.5.4.3, Page 52 
A qQualitative urine drug screen (UDS)ing will be performed at 
screening and Baseline (Day 1 before dosing) for all subjects, and 
at least every other day during in-clinic lofexidine treatment and 
outpatient treatment for the following drugs:  amphetamines/ 
methamphetamines, cocaine, barbiturates, opiates, benzodiazepines, 
cannabinoids, methadone, and buprenorphine.  The central lab will 
provide standard sets of UDS “dipsticks” for use across all 
sites.Urine will be sent to a central laboratory for qualitative 
analysis for drugs of abuse.  The methodology will detect specific 
drugs or metabolites in the urine. 
Revised to more fully monitor the safety of 
lofexidine.
Section 14.4.4.4, Page 35 
A “dip-stick” pregnancy test designed to measure human chorionic 
gonadotropin will be performed on the first day of screening for all 
subjects and on Day 14 or early completion/early termination for all 
female subjects regardless of their childbearing capacity.  Sites may 
use any FDA-approved urine pregnancy test. 
Section 15.5.4.4, Page 52 
A “dip-stick” pregnancy test designed to measure human chorionic 
gonadotropin will be performed on the first day of screeningfor all 
subjects, at Baseline (Day 1 before dosing), and on Day 14 or early 
completion/early termination at discontinuation from the study for 
all female subjects regardless of their childbearing capacity.  The 
central lab will provide study sites with a supply of pregnancy 
dipsticks.Sites may use any FDA-approved urine pregnancy test. 
Revised for consistency with companion 
study USWM-LX1-3003-1. 
-- 
Section 15.5.4.5, Page 52 
15.5.4.5  Pharmacokinetic Sampling 
A fingerprick blood sample will be collected concurrently with each 
scheduled ECG during the study. 
A fingerprick blood sample will be collected during outpatient 
treatment when the subject reports to the clinic each day (before 
next scheduled dose) for analysis of plasma lofexidine 
concentration to monitor compliance. 
Added to enable QTc-concentration 
analyses as well as to monitor compliance 
during outpatient treatment. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 208


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 88 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 14.4.5, Page 35 
A complete physical examination of the oral cavity, head, eyes, 
ears, nose and throat, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, neuropsychiatric mental status and 
sensory/motor status, musculoskeletal system, and general 
appearance should be performed at screening for all subjects, as 
clinically warranted during lofexidine treatment, and on Day 14 or, 
if applicable, early discharge/termination from the study. 
Height should be recorded at screening only. 
Section 15.5.5, Page 52 
A complete physical examination of the oral cavity, head, eyes, 
ears, nose and throat, cardiovascular system, lungs, abdomen 
(liver/spleen), extremities, skin, neuropsychiatric mental status and 
sensory/motor status, musculoskeletal system, and general 
appearance willshould be performed at screening for all subjects., 
as clinically warranted during lofexidine treatment, and on Day 14 
or, if applicable, early discharge/termination from the study. 
An update of the Physical Exam is required at Baseline (before 
dosing on Day 1) and then a complete physical examination should 
be performed 3 to 4 hours after the first dose on Day 1, as clinically 
warranted throughout the study, and at discontinuation from the 
study. 
Height should be recorded at screening only. 
Revised for consistency with study design 
changes. 
-- 
Section 15.5.6, Pages 52-53 
15.5.6  Columbia Suicide Severity Rating Scale (C-SSRS) 
[Section added.  See protocol.] 
Added for consistency with the current 
guidance to assess suicidality in all clinical 
studies involving central nervous system 
acting drugs. 
Section 14.5.1, Page 35, Second Paragraph 
-- 
Section 15.6.1, Page 53, Second Paragraph 
All opioids of abuse the subject has used will also be recorded at 
the screening visit. 
Administrative clarification. 
Section 14.5.2, Page 35 
Concomitant medication administration will be recorded at least 
every other day during the study.  All concomitant medications 
should be recorded on the Concomitant Medication eCRF.  The Site 
Investigator should treat the subject according to his/her usual 
standard of care for opioid withdrawal, with the exception that 
methadone is contraindicated for use in subjects taking lofexidine. 
Section 15.6.2, Page 53 
Concomitant medication administration will be recorded dailyat 
least every other day during the study.  All concomitant 
medications willshould be recorded in source and in the subject’s 
Concomitant Medication eCRF along with dose, dates of 
administration, and reason for use.The Site Investigator should treat 
the subject according to his/her usual standard of care for opioid 
withdrawal, with the exception that methadone is contraindicated 
for use in subjects taking lofexidine. 
Revised for consistency with changes made 
in other parts of the protocol. 
Section 15.1, Pages 35-36, Second and Third Sentences 
An Operations Manual will be provided to all investigational sites 
as a study quality assurance tool.  The monitoring of the sites 
participating in the trial will be executed according to GCP 
Section 16.1 Page 53, Second and Third Sentences 
An Investigator Site BinderOperations Manual will be provided to 
all investigational sites with additional instruction as well as a place 
to store regulatory and study documentsas a study quality assurance 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 209


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 89 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
guidelines. 
tool.  The monitoring of the sites participating in the trial (either 
remote or on site) will be executed according to GCP guidelines 
and with a focused data review approach (Risk Based Monitoring 
[RBM]). 
Section 15.4, Page 37, Second Paragraph, Fourth Sentence 
Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.   
Section 16.4, Page 54, Second Paragraph, Fourth Sentence 
Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.   
Revised to remove consent quiz, as deemed 
not essential for an open-label safety study. 
Section 15.6.1, Page 37 
The Sponsor’s (USWM) Medical Monitor will be responsible for 
attempting to establish concurrence with the Site Investigator on the 
severity and seriousness of any AEs and SAEs, the relatedness to 
the study treatments, the expectedness of the event, and for 
determining if the SAE should be reported to the FDA in a 7- or 
15-day expedited report or an annual report (Appendix 1).  The 
Sponsor’s Medical Monitor will also be responsible for tracking 
and assessing trends in the SAEs reported.  Further, the Medical 
Monitor is available to consult with the Site Investigators and 
coordinators on any medical issues related to the study 
(e.g., admission criteria, concomitant medications). 
Section 16.6.1, Page 55 
The Sponsor’s (USWM) Medical Monitors, 
 
will be responsible for 
attempting to establish concurrence with the Site Principal 
Investigator on the severity and seriousness of any AEs and SAEs, 
the relatedness to the study treatments, the expectedness of the 
event, and for determining if anthe SAE should be reported to the 
FDA in a 7- or 15-day expedited report or an annual report 
(Appendix 61).  The Sponsor’s Medical Monitor will also be 
responsible for tracking and assessing trends in the SAEs reported.  
Further, the Medical Monitor is available to consult with the Site 
Principal Investigators and coordinators on any medical issues 
related to the study (e.g., admission criteria, concomitant 
medications) and can be reached at 
 
and/or 
 
Administrative update to add
 
as back up Medical Monitor. 
Section 15.6.2, Page 37, First Paragraph 
All Investigators will allow the Sponsor or its representatives to 
periodically audit, at mutually convenient times during and after the 
study, all CRFs (paper and electronic) and corresponding source 
documents for each subject.  These monitoring visits will provide 
an opportunity for evaluation of the progress of the study and to 
inform the Sponsor of potential problems. 
Section 16.6.2, Page 55, First Paragraph 
All Investigators will allow the Sponsor or its representatives to 
periodically audit, at mutually convenient times during and after the 
study, all eCRFs (paper and electronic) and corresponding source 
documents as noted in the monitoring plan for each subject.  Using 
an RBM approach, monitoring may also occur remotely.  These 
monitoring visitsMonitoring both on site and via an RBM approach 
will provide an opportunity for evaluation of the progress of the 
study and to inform the Sponsor of potential problems. 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 210


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
Confidential Information 
Page 90 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2, 
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number) 
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 15.6.2, Page 38, Third Paragraph 
Monitors will conduct a site initiation visit before the start of the 
study.  At this visit, the monitor will assure that proper study-
related documentation exists, assist in training investigators and 
other site personnel in study procedures and GCP guidelines, 
confirm receipt of study supplies, and assure that acceptable 
facilities are available to conduct the study. 
Section 16.6.2, Page 55, Third Paragraph 
In lieu of an investigator meeting, USWM will host a web-based 
initiation meeting with study sites providing at a minimum protocol 
training, GCP training, CRF completion training, and a review of 
monitoring expectations.  For sites that did not participate in study 
USWM-LX1-3003-1, mMonitors will additionally conduct a site 
initiation visit before the start of the study.  At this visit, the 
monitor will assure that proper study-related documentation exists, 
assist in training investigators and other site personnel in study 
procedures and GCP guidelines, confirm receipt of study supplies, 
and assure that acceptable facilities are available to conduct the 
study. 
Administrative change. 
Section 15.6.2, Page 38, Fourth Paragraph, First Sentence 
Routine monitoring visits by USWM will be scheduled at 
appropriate intervals but more frequently at the beginning of the 
study.  At these visits, the monitors will verify that study 
procedures are being conducted according to the protocol 
guidelines and review AEs and SAEs. 
Section 16.6.2, Page 55, Fourth Paragraph, First Sentence 
PeriodicRoutine monitoring visits by USWM will be scheduled at 
appropriate intervals.but more frequently at the beginning of the 
study.  At these visits, the monitors will verify that study 
procedures are being conducted according to the protocol 
guidelines and review AEs and SAEs. 
Administrative clarification. 
Section 15.7, Page 38, First Paragraph, Last Sentence 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol. 
Section 16.7, Page 56, First Paragraph, 2nd, 3rd, & 4th Sentences 
The occurrence of AEs will be assessed starting at the treatment 
phase of the protocol (i.e., with the first dose of study drug).  Any 
AE that occurs during screening will be recorded in the subject’s 
Medical History eCRF.  The occurrence of Serious Adverse Events 
(SAEs) will be assessed after signing of the informed consent form. 
Administrative clarification. 
Section 15.7, Page 38, Second Paragraph 
An AE is defined as any reaction, side effect, or untoward event 
that occurs during the course of the clinical trial, whether or not the 
event is considered related to the investigational agent or clinically 
significant.  For this study, events reported by the subject, as well 
as clinically significant abnormal findings on physical examination 
or laboratory evaluation will be recorded on the AE eCRF.  A new 
illness, symptom, sign or clinically significant clinical laboratory 
abnormality or worsening of a pre-existing condition or 
abnormality is considered an AE.  Stable chronic conditions, such 
Section 16.7, Page 56, Second Paragraph 
An AE is defined as any reaction, side effect, or untoward event 
that occurs during the course of the clinical trial, whether or not the 
event is considered related to the investigational agent or clinically 
significant.  For this study, events reported by the subject, as well 
as clinically significant abnormal findings in the opinion of the 
Principal Investigator on physical examination, or laboratory 
evaluation, or C-SSRS (for example, score of 3 or more on the 
scale) will be considered an AE and will be recorded on the AE 
eCRF.  A new illness, symptom, sign or clinically significant 
Administrative clarification/update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 211


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 91 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
as arthritis, which are present before clinical trial entry and do not 
worsen are not considered AEs. 
clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE.  Opioid withdrawal 
symptoms experienced by subjects during screening will be 
recorded on the Medical History eCRF and such symptoms will be 
recorded as AEs during the study even if they do not change or 
worsen.  Stable chronic conditions, such as arthritis, which are 
present before entry into the clinical trial and do not worsen are not 
considered AEs. 
Section 15.7, Page 38, Third Paragraph, 1st & 2nd Sentences 
After each AE assessment, the physician will record on the AE 
eCRF the type of AE and whether serious (SAE) or non-serious, 
severity of each AE, and the relationship to the study agent.  These 
categories are asking for the physician’s best judgment of the 
severity and relatedness of each AE.   
Section 16.7, Page 56, Third Paragraph, 1st & 2nd Sentences 
ForAfter each daily AE assessment, the physician details will be 
recorded in the subject’s source document and on theAE eCRF 
regarding the type of AE and whether serious (SAE) or non-serious, 
severity of each AE, and the relationship to the study agent.  These 
categories are asking for the Principal Investigator or physician 
designee’s best judgment of the severity and relatedness of 
each AE. 
Administrative clarification. 
Section 15.9, Page 40 
Although pregnancy is not considered an AE, it is the responsibility 
of the Site Investigator or his or her designee to report any 
pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs 
during the study or within 30 days of completing the study 
medication.  All subjects who become pregnant must be withdrawn 
from study medication and must be followed to the 
completion/termination of the pregnancy.  If the pregnancy 
continues to term, the outcome (health of infant) must also be 
reported to the Sponsor. 
Section 16.9, Page 57 
Although pregnancy is not considered an AE, it is the responsibility 
of the PrincipalSite Investigator or his/or her designee to report any 
pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs 
during the study or within 30 days of takingcompleting the study 
medication.  All subjects who become pregnant must be withdrawn 
from the study and stop taking study medication.  and must be 
followed to the completion/ termination of the pregnancy.  The site 
must make appropriate effort (i.e., monthly calls) to follow the 
subject until completion/termination of the pregnancy.  If the 
pregnancy continues to term, the outcome (health of infant) must 
also be reported to the Sponsor. If the subject cannot be reached 
after 3 telephone attempts, a certified letter should be sent.  
Documentation of follow-up will be recorded in the source 
documents. 
Administrative update. 
Section 16.2, Page 40, Fourth Bullet 
• Subjects completing final buprenorphine withdrawal; 
Section 17.2, Page 58, Fourth Bullet 
• Subjects completing final buprenorphine withdrawal; 
Revised to improve clarity of the protocol. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 212


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 92 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 16.2, Page 41, Bulleted Items 
Descriptive statistics will be provided for: 
• Demographics and baseline characteristics; 
• COWS numerical score; 
• COWS severity category (i.e., mild, moderate, moderately 
severe, severe); 
• Duration of exposure to lofexidine; 
• Number of subjects successfully completing planned 
detoxification/transition as assessed by the Site Investigator; 
• Distribution of number of days required to complete 
detoxification; 
• Average daily dose of lofexidine; 
• Concomitant medications; 
• Linkage to long-term care (through subject treatment status report 
at the 30-day post discharge follow-up telephone contact); and 
• Compliance in taking lofexidine (based on pill counts). 
Section 17.2, Pages 58-59, Bulleted Items 
Descriptive statistics will be provided for: 
• Demographics and baseline characteristics; 
• SOWS-Gossop; 
• COWS numerical score; 
• COWS severity category (i.e., mild, moderate, moderately 
severe, severe); 
• Duration of exposure to lofexidine; 
• Number/proportion of subjects successfully completing the pre-
defined withdrawal treatment goal (e.g., planned 
detoxification/transition) as assessed by the Site Principal 
Investigator; 
• Distribution of number of days required to complete withdrawal 
treatment goal by categorydetoxification; 
• Average daily dose of lofexidine; 
• Concomitant medications; and 
• Linkage to long-term care (throughEvaluation of subject 
treatment statusreport at the 30 -days after last dose.post 
discharge follow-up telephone contact).; and 
• Compliance in taking lofexidine (based on pill counts). 
Revised for consistency with study design 
changes. 
Section 16.3, Page 41, Bulleted Items 
Safety measures will be summarized for the following subject 
cohorts: 
• All treated subjects; 
• Treated subjects without urinary evidence of illicit drug use; and 
• Treated subjects with urinary evidence of illicit drug use (may be 
further subdivided by type of illicit drug used). 
Descriptive statistics will be provided for: 
• AEs; 
• Vital signs; 
• ECGs; and 
• Clinical laboratory tests. 
Section 17.3, Page 59, Bulleted Items 
Safety measures will be summarized for the following subject 
cohorts: 
• All exposed subjects; 
• Subjects undergoing abrupt and total withdrawal; 
• Subjects undergoing buprenorphine-assisted withdrawal; 
• Subjects transitioning to naltrexone maintenance;  
• Subjects transitioning to buprenorphine maintenance; 
• Subjects undergoing partial withdrawal to lower dose (e.g., 
chronic opioid medication for pain); and 
• Any other identifiable cohorts not otherwise noted. 
• All treated subjects; 
• Treated subjects without urinary evidence of illicit drug use; and 
Revised for consistency with study design 
changes. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 213


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 93 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
• Treated subjects with urinary evidence of illicit drug use (may be 
further subdivided by type of illicit drug used). 
 
Descriptive statistics will be provided for: 
• AEs; 
• AEs of special interest, including orthostatic hypotension, 
orthostatic bradycardia, and syncope; 
• Vital signs; 
• ECGs; and 
• Clinical laboratory tests; and 
• C-SSRS. 
Section 17, Page 42 
Data management activities and statistical analytical support will be 
coordinated through the CRO (TBD).  The CRO will be responsible 
for the construction and accuracy of the study database. 
Section 18, Page 59 
Data management activities, construction and accuracy of the study 
database, and statistical analytical support will be coordinated 
through USWM.the CRO (TBD).  The CRO will be responsible for 
the construction and accuracy of the study database. 
Administrative change. 
Section 17.1, Page 42, First Paragraph 
Data will be collected at the study sites on source documents, which 
will be entered at the site into electronic CRFs (eCRFs), except for 
the COWS assessment, which is a validated paper instrument and 
thus will be collected on paper, scanned, and appended to the 
subject’s eCRF for entry into the database.  The eCRFs and paper 
CRFs will be supplied by the CRO.  CRFs are to be completed on 
an ongoing basis during the study.  The medical chart and the 
source documents are the source of verification of data.  CRFs 
should be completed according to the instructions in the study 
operations manual. 
Section 18.1, Pages 59-60, First Paragraph 
Data will be collected at the study sites on source documents, which 
will be entered at the site into electronic CRFs (eCRFs).,  except for 
the COWS assessment, which is a validated paper instrument and 
thus will be collected on paper, scanned, and appended to the 
subject’s eCRF for entry into the database.The eCRFs and paper 
CRFs will be supplied by the CRO.  CRFs are to be completed on 
an ongoing basis during the study within 2 to 3 business days of a 
visit.  The medical chart and the source documents are the source of 
verification of data.  CRFs should be completed according to the 
instructions in the Investigational Site File binderstudy operations 
manual. 
Administrative change. 
Section 17.1, Page 42, Third Paragraph 
Data generated by this study must be available for inspection by 
representatives of the US FDA, the Sponsor (USWM), the Sponsor 
representatives, and the site’s IRB. 
Section 18.1, Page 60, Third Paragraph 
Data generated by this study must be available for inspection by 
representatives of the US FDA, the Sponsor (USWM), the 
Sponsor’s representatives, the central IRB 
 orand the site’s 
IRB. 
Administrative update. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 214


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 94 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
Section 17.2, Page 42 
Section 18.2, Page 60 
18.2 Electronic Data CaptureData Processing, Editing, and 
Control 
[Section extensively revised.  See protocol for changes.] 
Administrative change. 
Section 17.5.2, Page 44, First Paragraph, First and Second 
Sentences 
To maintain subject confidentiality, all laboratory specimens, CRFs 
(electronic or paper), reports, and other records will be coded using 
alpha-numeric identifiers only.  Only research and clinical records 
will be stored in a locked cabinet. 
Section 18.5.2, Page 61, First Paragraph, First and Second 
Sentences 
To maintain subject confidentiality, all laboratory specimens, CRFs 
(electronic or paper), reports, and other records will be coded using 
subject number and initials.alpha-numeric identifiers only.  Only 
research and clinical records will be stored in a locked cabinet. 
Administrative change. 
Section 18, Pages 44-45 
18. PUBLICATIONS OF THE STUDY RESULTS 
It is understood by the Site Investigator that the information 
generated in this study will be used by the Sponsor (USWM) in 
connection with the development of the product and therefore may 
be disclosed to government agencies in various countries.  To allow 
for the use of information derived from the study, it is understood 
that the Site Investigator is obliged to provide the Sponsor with 
complete test results, all study data, and access to all study records. 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages their publication in reputable 
scientific journals and at seminars or conferences.  Because this is a 
multicenter study, the combined results of the study will be 
published before the Investigator submits site-specific results for 
publication.  Any results of medical investigations with the 
Sponsor’s products and/or publication/lecture/manuscripts based 
thereon, shall be exchanged and discussed by the Site Investigator 
and Sponsor representative(s) 60 days before submission for 
publication or presentation.  Due regard shall be given to the 
Sponsor’s legitimate interests, e.g., manuscript authorship, 
obtaining optimal patent protection, coordinating and maintaining 
the proprietary nature of submissions to health authorities, 
coordinating with other ongoing studies in the same field, and 
Section 19, Page 61 
19. DISSEMINATION AND PUBLICATIONS OF THE 
STUDY RESULTS 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages theirpublication of such data in 
reputable scientific journals and at seminars or conferences.  The 
details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study is 
described in the Clinical Trial Agreement between the Sponsor and 
the institution of the Investigator. 
It is understood by the Site Investigator that the information 
generated in this study will be used by the Sponsor (USWM) in 
connection with the development of the product and therefore may 
be disclosed to government agencies in various countries.  To allow 
for the use of information derived from the study, it is understood 
that the Site Investigator is obliged to provide the Sponsor with 
complete test results, all study data, and access to all study records. 
The Sponsor recognizes the importance of communicating medical 
study data and therefore encourages their publication in reputable 
scientific journals and at seminars or conferences.  Because this is a 
multicenter study, the combined results of the study will be 
published before the Investigator submits site-specific results for 
publication.  Any results of medical investigations with the 
Sponsor’s products and/or publication/lecture/manuscripts based 
Administrative clarification. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 215


Protocol No. USWM-LX1-3003-2, Amendment No. 01 
January 22, 2015 
 
Confidential Information 
 
Page 95 of 113 
Table 4. 
Changes for USWM-LX1-3003-2 Protocol (February 3, 2012)    USWM-LX1-3003-2,  
Amendment No. 01 (January 22, 2015) 
Location (Section and Page Number)  
and Previous Wording 
Location (Section and Page Number) 
Revised Text in Blue and Deleted Text in Red 
Rationale 
protecting confidential data and information. 
The Sponsor shall be furnished with a copy of any proposed 
publication.  In cases of publications or presentations of material 
arising from multicenter clinical investigations, the Sponsor is to 
serve as coordinator and referee.  Individual investigators who are 
part of a multicenter investigation may not publish or present data 
that are considered common to a multicenter investigation without 
the consent of the other participating investigators and the prior 
review of the Sponsor.  In case of disagreement amongst the 
investigators participating in a multicenter investigation, the 
Sponsor will be the final arbiter.  Sponsor comments shall be given 
without undue delay, and not later than within 60 days.  If they are 
not accepted, the senior author of the manuscript and the Sponsor’s 
representatives shall promptly meet to discuss further and endeavor 
to agree on the final wording and/or disposition of the publication.  
The above procedure also applies to studies that are not completed, 
including those that are prematurely discontinued. 
Results from investigations shall not be made available to any third 
party by the investigating team outside the publication procedure as 
outlined previously.  The Sponsor will not quote from publications 
by investigators in its scientific information and/or promotional 
material without full acknowledgment of the source (i.e., author and 
reference). 
thereon, shall be exchanged and discussed by the Site Investigator 
and Sponsor representative(s) 60 days before submission for 
publication or presentation.  Due regard shall be given to the 
Sponsor’s legitimate interests, e.g., manuscript authorship, 
obtaining optimal patent protection, coordinating and maintaining 
the proprietary nature of submissions to health authorities, 
coordinating with other ongoing studies in the same field, and 
protecting confidential data and information. 
The Sponsor shall be furnished with a copy of any proposed 
publication.  In cases of publications or presentations of material 
arising from multicenter clinical investigations, the Sponsor is to 
serve as coordinator and referee.  Individual investigators who are 
part of a multicenter investigation may not publish or present data 
that are considered common to a multicenter investigation without 
the consent of the other participating investigators and the prior 
review of the Sponsor.  In case of disagreement amongst the 
investigators participating in a multicenter investigation, the 
Sponsor will be the final arbiter.  Sponsor comments shall be given 
without undue delay, and not later than within 60 days.  If they are 
not accepted, the senior author of the manuscript and the Sponsor’s 
representatives shall promptly meet to discuss further and endeavor 
to agree on the final wording and/or disposition of the publication.  
The above procedure also applies to studies that are not completed, 
including those that are prematurely discontinued. 
Results from investigations shall not be made available to any third 
party by the investigating team outside the publication procedure as 
outlined previously.  The Sponsor will not quote from publications 
by investigators in its scientific information and/or promotional 
material without full acknowledgment of the source (i.e., author and 
reference). 
Section 21, Page 46 
-- 
Section 22, Pages 62-63 
[Reference list updated.  See protocol.] 
Administrative change. 
209229
uswm-lx1-3003-2-protocol-and-amendments
 Pg. 216

SAP_001.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
STATISTICAL ANALYSIS PLAN PROTOCOL NUMBER: USWM-LX1-3003-2 / 02 
 
  
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
 
 
TITLE: 
A Phase 3, Open-Label, Safety Study of Lofexidine 
 
 
DOCUMENT DATE: 06APR2016 
NDA NUMBER: 209229 
NCT NUMBER: NCT02363998 


US WorldMeds, LLC 
209229 
Clinical Study Report – USWM-LX1-3003-2 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
Table 1: 
Statistical Analysis Plans 
Statistical Analysis Plans Included in Appendix 16.1.9 
16.1.9.1 Statistical Analysis Plan: Clinical Study Report- Version 1.0- 06 April 2016 
uswm-lx1-3003-2-documentation-of-statistical-methods 
Pg. 1 


 
Protocol Number: USWM-LX1-3003-2 
Final Version: 1.0 
Issue Date: 06-APR-2016 
 
 
 
 
   Page 1 of 19 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
                                                                                                                                                                               
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
USWM-LX1-3003-2 
A Phase 3, Open-Label, Safety Study of Lofexidine 
 
Protocol Ref: USWM-LX1-3003-2 
Final Version: 1.0 
Date effective:  06-APR-2016 
 
 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 2


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 2 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
SUMMARY OF SECTIONS 
1.
INTRODUCTION ............................................................................................................... 3 
2.
SAMPLE SIZE.................................................................................................................... 6 
3.
RANDOMIZATION ............................................................................................................ 6 
4.
INTERIM ANALYSIS ......................................................................................................... 6 
5.
Statistical methods ............................................................................................................... 6 
5.1 
Continuous .................................................................................................................. 6 
5.2 
Categorical .................................................................................................................. 6 
6.
Analysis Plan ...................................................................................................................... 6 
6.1 
General........................................................................................................................ 6 
6.2 
Derived Data ................................................................................................................ 7 
6.3 
Analysis populations ..................................................................................................... 7 
6.4 
Protocol Deviations ....................................................................................................... 8 
6.5 
Data Summaries ........................................................................................................... 8 
6.6 
Disposition of Subjects .................................................................................................. 8 
6.7 
Baseline Comparability ................................................................................................. 8 
6.7.1 
Study Population ................................................................................................... 8 
6.7.2 
Variables Considered ............................................................................................. 9 
6.8 
Effectiveness Endpoints............................................................................................... 11 
6.9 
Safety analysis ........................................................................................................... 12 
6.10 
Change to Planned Protocol Analysis ............................................................................ 17 
6.11 
References ............................................................................................................... 17 
7.
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................................... 18 
8.
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................................. 18 
9.
APPENDIX 16.2 LISTINGS ............................................................................................... 18 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 3


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 3 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
1.  INTRODUCTION 
This document details the statistical analysis of the data that will be performed by 
 
 for the US WorldMeds, LLC study USWM-LX1-3003-2.  
 
The proposed analysis is based on the contents of the Final Version of the protocol (dated 03-
Feb-2012) and amendments 1 and 2 (dated 22-Jan-2015 and 21-May-2015 respectively). 
 
The primary objective of the study is to continue to investigate the safety of lofexidine when 
administered for at least 7 days at clinically relevant doses (3.2 or 2.4 mg/day) to alleviate 
symptoms of acute withdrawal from opioids in a variety of clinical scenarios in both in-clinic 
and outpatient settings. The effectiveness of lofexidine is also of interest. 
 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 4


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 4 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
Table 1. Schedule of Study Assessments 
 
Activity 
Screening 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
End of Study* 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
Informed Consent Signed 
X 
Subject Number Assigned 
X 
Inclusion/Exclusion Criteria 
X 
X (b) 
Prior Medication History 
Past 30 days 
X (b) 
Demographics 
X 
Medical and Smoking History 
X 
Mini-International Neuropsychiatric Interview 
X 
Infectious Disease Assessments (c) 
X 
Chest X-Ray (c) 
X 
Pregnancy Test (d) 
X 
X 
X 
Height 
X 
Weight 
X 
X 
Complete Physical Exam 
X 
X (b) 
X (e) 
As needed 
As needed 
X 
Admission to In-clinic Facility 
X (f) 
Study Medication Administration 
X (QID) 
X (QID) (g) 
Optional 
Medication Compliance 
X 
X 
X 
X 
Study Medication Taper 
X 
Discharge from In-clinic Facility 
Variable, but by Day 7 
Clinic Visit 
Daily if outpatient 
Daily 
Issue Subject Diary 
Daily if outpatient 
Daily 
12-Lead Electrocardiogram (duplicate) 
X (h) 
X (i) 
X (i) 
X (j) 
Urine Drug Screen (k) 
X 
X 
X 
X 
X 
X 
Vital Signs (Sitting/Recumbent & Standing BP 
and pulse; respiration; and temperature) 
X 
X 
X (l) 
X (l) (m) 
X (m) 
X 
Clinical Laboratory Tests (hematology, 
chemistry, urinalysis) 
X 
As needed 
As needed 
As needed 
As needed 
X 
Adverse Events Assessment 
X 
X 
X 
X 
C-SSRS Baseline Version 
X 
C-SSRS Since Last Visit Version 
X (n) 
X (n) 
X (n) 
X 
Short Opiate Withdrawal Scale of Gossop (o) 
X 
X 
X 
X 
X 
Clinical Opiate Withdrawal Scale (COWS) (o) 
X 
X 
X 
X 
X 
Fingerprick Blood Sample 
X (p) 
X (q) 
X (p) (q) 
X (p) 
Concomitant Medications Assessment 
X 
X 
X 
X 
 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 5


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 5 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
Table 1. Schedule of Study Assessments 
 
Activity 
Screening 
Baseline (a) 
In-clinic 
Treatment 
In-clinic/Outpatient 
Treatment 
Outpatient 
Treatment 
Study 
Discontinuation/ 
End of Study* 
Days -8 to -1 
Day 1 
Days 1-3 
Days 4-7 
Days 8-14 
Define Subject-Specific Withdrawal 
Treatment Goal 
X 
 
Assessment of Completion of Pre-defined 
Withdrawal Treatment Goal (r) 
X 
X 
X 
X 
Telephone Follow Up Contact 
X (s) 
Abbreviations:  BP = blood pressure, C-SSRS = Columbia Suicide Severity Scale, PK = pharmacokinetic, PPD = purified protein derivative, QID = 4 times daily 
* 
The study discontinuation/end of study assessments/procedures should always be done when subject exits from the study. (a)   
The Baseline period is the morning of admission, before dosing. 
(b)   This form is to be updated at Baseline. 
(c)   A chest x-ray is required only if a PPD skin test for tuberculosis is not done, the current PPD is positive, or if a past PPD was positive. 
(d)   The urine sample collected on the first day of screening will be divided into two aliquots.  One sample will be sent to the central lab 
) for 
urinalysis and the other sample will be used for urine drug screening and immediate “dipstick” analysis of pregnancy (females only). 
(e)   A complete physical exam will be done on Day 1 (3-4 hours after first dose) and as clinically warranted. 
(f)   Subjects may be admitted to the hospital or clinic in the evening (Day -1) before study drug administration on Day 1. 
(g)   Per Investigator judgment, subjects can be discharged from the study after receipt of at least one dose of study drug on Day 7 and after completion of all end-of-study procedures. 
(h)   Baseline 12-lead electrocardiograms (ECGs) will be done on one day during the screening period at 8 AM (or as close to 8 AM as possible) and at 11:30 AM.  Note that a time 
delay for the 8 AM ECG will not be considered a protocol deviation, but that the second ECG should be taken 3.5 hours after the first ECG. 
      (i)    12-lead ECGs (duplicate) before dosing on Day 1 at 8 AM and 3.5 hours (± 15 minutes) after dosing. 
(j)    12-lead ECGs (duplicate) before subject’s  last dose and 3.5 hours after dosing (or as close to this time as possible) or, if applicable, at discontinuation from the study. 
(k)   Urine drug screen will be done every day in an in-clinic setting to monitor for contraband and every day in an outpatient setting to monitor illicit drug use. 
(l)    During in-clinic treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured before every 
dose and 3.5 hours after study medication administration at 8 AM, 1 PM, and 6 PM; respiration and temperature before 8 AM dose only. 
(m)  During outpatient treatment, resting (sitting [or recumbent if necessary because of an adverse event]) and standing (if able) blood pressure and pulse will be measured before an in- 
clinic dose of lofexidine each day and 3.5 hours after dosing on Days 4-13 and once before any dose on Day 14 and at the End of Treatment/Study Discontinuation visit.  Oral 
temperature and respiration are not required measurements during outpatient treatment. 
(n)   C-SSRS will be completed 3.5 hours after the first dose (8 AM) during in-clinic treatment or once daily before an in-clinic dose of lofexidine during outpatient treatment. 
(o)   During in-clinic treatment, effectiveness scales will be completed once daily:  the Short Opiate Withdrawal Scale of Gossop 3.5 hours (±10 minutes) after the first dose of study 
medication followed by COWS, and the assessment of completion of pre-defined withdrawal treatment goal.  Effectiveness scales will be completed daily before an in-clinic dose of 
lofexidine during outpatient treatment. 
(p)   A fingerprick blood sample for PK analysis will be collected concurrently with each scheduled ECG. 
(q)   A fingerprick blood sample will be collected during outpatient treatment when the subject reports to the clinic each day (before next scheduled dose) for analysis of plasma 
lofexidine concentration to monitor compliance. 
(r)   This form is to be completed by the Principal Investigator after completion of the SOWS-Gossop and COWS. 
(s)   A follow-up telephone contact will be attempted 30 days after the subject’s last dose and will include an adverse event evaluation and an evaluation of the subject’s current 
     treatment status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, buprenorphine, or naltrexone program). 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 6


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 6 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
2. SAMPLE SIZE
The total enrollment in this study will depend on subject drop-out rates in this protocol. 
Enrollment will continue until a minimum total of 300 subjects (across this protocol and 
earlier lofexidine clinical studies expected to meet FDA safety database requirements) have 
been treated with clinically relevant doses of lofexidine for a minimum of 7 days.  It is 
estimated that approximately 250 to 500 subjects will be enrolled in this open-label study in 
order to accrue a sufficiently large safety database for evaluation. 
3. RANDOMIZATION
No randomization was performed. 
4. INTERIM ANALYSIS
No interim analysis is planned. 
5. STATISTICAL METHODS
5.1 Continuous 
Continuous variables and ordered categorical variables not subject to censoring will be 
summarized with the number of non-missing observations, mean, standard deviation, minimum, 
25th percentile, median, 75th percentile, and maximum.  
For summary statistics, means, medians and percentiles will be displayed to one more decimal 
place than the raw data, dispersion statistics (e.g. standard deviation) will have two more 
decimal places, and the minimum and maximum will be displayed to the same number of 
decimal places as reported in the raw data. 
5.2 Categorical 
Unordered categorical and ordered categorical (depending on the number of categories) 
variables will be presented in contingency tables with cell frequencies and percentages for the 
number of non-missing observations and frequencies for the number of missing observations 
apart from disposition of subjects, concomitant medications, measurement of treatment 
compliance and adverse events where percentages will be presented for the population. 
6. ANALYSIS PLAN
6.1 General 
The treatment will be labelled as Lofexidine for presentation of efficacy and safety data. 
Subject data in Appendix 16.2 listings will be ordered by treatment, site, subject, and study day 
when applicable. 
All tabulations, data listings and figures will be produced using SAS Version 9.31 or higher. 
All summaries and analyses documented below will be presented in the final integrated 
statistical/clinical report and tables that will be based on the E3 guidelines published by ICH.  
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 7


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 7 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
However, it is noted here that no analysis plan prepared in advance of the data can be 
absolutely definitive and so the final report may contain additional tables or statistical tests if 
warranted by the data obtained.  The justification for any such additional analyses will be fully 
documented in the final report. 
6.2 Derived Data 

Definition of baseline
With the exception of vital signs measurements, baseline is defined as the last non-missing 
value prior to the receiving the first dose of study medication. For vital signs measurements, the 
last screening measurement will be used as baseline. 
All tabulations involving change from baseline data will only include subjects with cohort data 
i.e. with data at baseline and at follow-up. Change from baseline will be calculated as follow-up
values minus baseline value.

Incomplete dates
All incomplete dates will be included in the clinical database as they were entered in the eCRF.  
Thereafter for calculation purposes, the incomplete dates will be completed using pre-defined 
rules.  If a day or month is not recorded it will be replaced by the first day of the month or 
January respectively, provided this does not contradict any other dates recorded.  For missing 
adverse events and medications dates/times during the trial, the worst-case date will be used 
(e.g. the end of the month for a stop date and 23:59 for the stop time, the date/time of initial 
dose for start of AE i.e. all events with missing start dates will be assumed to be treatment 
emergent). 

Ambiguous values
In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x”, then for analysis purposes 
a value of x will be taken. Where a range of values is quoted the midpoint of the range will be 
taken.  

Questionnaire Data
In the event that component items used to calculate total scores for questionnaire data e.g. 
SOWS Gossop score are missing then the total scores will also be set to missing. 
6.3 Analysis populations 
The Enrolled Population includes all subjects screened into the study irrespective of whether 
they received the study medication. 
The Safety Population includes all subjects who received at least one dose of study medication. 
With the exception of the disposition table all outputs will use the Safety Population.  
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 8


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 8 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
6.4 Protocol Deviations 
A listing of protocol deviations will be provided within Appendix 16.2. 
6.5 Data Summaries 
The data will be summarized in tabular form by treatment (Lofexidine). 
Graphical presentations of the data will also be provided where appropriate. 
6.6 Disposition of Subjects 
The following will be summarized: 

The number of subjects who are included in the Enrolled Population,

The number of enrolled subjects that enrolled but failed to be dosed along with the
reasons,

The number of subjects that completed the inpatient treatment period and the number of
subjects who transitioned to outpatient at Day 4, 5, 6 and 7 (each day will be displayed
separately).

The number of enrolled subjects that completed the study (took one dose on Day 7).
Additionally, the reason for withdrawal will be summarized as follows:
o
Lack of effectiveness
o
AE related to study drug
o
Withdrew consent
o
Lost to Follow-Up
o
AE unrelated to the study drug or withdrawal symptoms (e.g. concomitant illness)
o
There is evidence of contraband drug use while participating in the study
o
Requires treatment with an exclusionary drug
o
Lack of compliance with protocol and/or unit procedures
o
Other, specify
6.7 Baseline Comparability 
6.7.1 Study Population 
Subject demographics and baseline characteristics will be presented for all subjects within the 
Safety Population. 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 9


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 9 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
Co-administration categories will include the following: 
 Any co-administration of Buprenorphine 
 Any co-administration of Methadone 
 Other (no co-administration of buprenorphine or methadone) 
6.7.2 Variables Considered 
Standard continuous or categorical variable summaries will be presented for the following 
variables: 
Demography  
 
Site number 
 
Age at screening visit as recorded on the study database (years) 
 
Sex (Male, Female) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other). If more than one race is selected then 
race will be “Other”. 
 
Height (cm) at Screening visit 
 
Body weight (kg) at Screening visit 
 
BMI (kg/m2), at Screening visit, calculated as weight (kg) divided by height (m2) rounded 
to one decimal place. 
Medical History  
Separate tabulations will be produced for previous and ongoing conditions with all conditions 
coded using MedDRA Version 18.0 (primary system organ class and preferred term). 
Smoking & Alcohol History  
 Ever smoked cigarettes (Yes, No). If yes, 
o Number of years used 
o Average number of times used/day 
o Whether currently smoking (Yes, No) 
 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 10


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 10 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
Alcohol History  
 Was Alcohol ever used? (Yes, No). If yes, 
o Number of years alcohol was used (Yes, No)  
o Currently using (Yes, No) 
o Average number of times consumed/week 
Opioids Abuse  
 Primary Opioid of Abuse (data recorded on the concomitant medication eCRF) 
 Duration of substance abuse (years).  
 
Average number times taken per day. 
 
IV Use (Yes/No) 
Infectious Disease Panel and Syphilis Tests at Screening  
 
Syphilis Antibody (Positive, Negative) 
 
HBsAg (Reactive, Non-reactive) 
 
Anti-HBc, Total (Reactive, Non-reactive) 
 
Hep B Surface Ab (IU/L) 
 
Anti-HCV (Reactive, Non-reactive) 
Urine Drug Screen at Screening  
 
Result, positive for: 
o 
Amphetamines (Yes, No) 
o 
Methamphetamines (Yes, No) 
o 
Cocaine (Yes, No) 
o 
Barbiturates (Yes, No) 
o 
Opiates (Yes, No) 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 11


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 11 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
o
Benzodiazepines (Yes, No)
o
Cannabinoids (Yes, No)
o
Methadone (Yes, No)
o
Buprenorphine (Yes, No)
o
Oxycodone (Yes, No)
o
Phencyclidine (Yes, No)
o
MDMA (Yes, No)
Prior medications 
Verbatim terms (as recorded on the CRFs) of medications that ceased prior to the time of the 
initial dose of study medication will be mapped to Anatomical Therapeutic Chemical (ATC) 
Level 2 and Drug Reference Names using the World Health Organization (WHO) dictionary 
(Version 6.2015 Enhanced). Prior medications will be listed in Appendix 16.2. 
  Measurement of Treatment Compliance 
Details of compliance will be tabulated overall and for each co-administration category by 
study day. 
Additionally, lofexidine concentration data will be summarized by descriptive statistics for 
each study day. 
6.8 Effectiveness Endpoints 
Treatment Goal 
Number and proportion of subjects’ baseline treatment goal will be presented overall and for 
each co-administration category. 
Status of Pre-defined Withdrawal Treatment Goal as Assessed by the Site Investigator 
Number and proportion of subjects successfully completing their pre-defined withdrawal 
treatment goal as assessed by the Site Investigator at Day 7 or early termination (last 
assessment) and Day 14 will be presented overall and for each co-administration category.  The 
number and proportion of subjects who relapsed during the study will be presented overall by 
study day. 
Questionnaires 
Summary statistics will be provided overall and for each co-administration category by study 
day for Days 1-14: 

SOWS-Gossop
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 12


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 12 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
COWS  
Concomitant Medications 
For each of Days 1 to 14, each subject’s number of concomitant medication taken will be 
treated as a continuous variable. Descriptive statistics will be provided on the as-observed data 
on each study day and also overall study days.  
Details of the Day 30 Follow-Up  
 Lost to Follow-up 
 Whether subject entered one of the following programs: 
o None 
o Methadone 
o Buprenorphine 
o Naltrexone 
o Other 
 Whether subject relapsed to drug use after exiting the study (Yes, No) 
6.9 Safety analysis 
Safety measures will be summarized for the following: 
 Safety Population 
 Co-administered Buprenorphine; 
 Co-administered Methadone 
 Other (no co-administration of buprenorphine or methadone) 
 and 
 Any other identifiable co-administration categories not otherwise noted. 
Extent of exposure 
Extent of exposure will be described by whether the subject took the trial medication and the 
number of days’ exposure (last date of medication minus first date of medication + 1). Average 
daily dose of study medication will also be calculated. No allowance will be made for breaks in 
therapy in the exposure calculations. If the date of last dosing is completely missing for the trial 
medication then the date of last dosing will be taken for analysis purposes as the date the 
medication was last dispensed.  If only the month of the last dose is recorded, the first day of 
the month will be assumed as the last dosing date. 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 13


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 13 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
Additionally, the number and percentage of subjects with a dose reduction from 3.2 mg/day to 
2.4 mg/day will be presented overall and for each co-administration category by study day. 
Adverse Events 
All AEs will be listed and tabulated by severity, relationship to study medication, primary 
system organ class and preferred term according to MedDRA Version 18.0.  In counting the 
number of events reported, a continuous event, i.e., an event reported more than once and 
which did not cease, will be counted only once with the worst recorded severity; non-
continuous AEs reported several times by the same subject will be counted as multiple events.  
Events present immediately prior to the first dose of study medication that do not worsen in 
severity, will not be regarded as treatment emergent.  Events with start dates more than 30 days 
after the administration of the last dose of study medication will not be considered treatment 
emergent and will be listed separately.  In deriving the tabulation relating to preferred term 
reporting, the severity of a recurrent AE will be taken to be the most severe and the relationship 
to study medication as the highest probable.  Missing or incomplete TEAE start dates will be 
imputed to correspond with the date of dosing.  
 
The following will be summarized and presented for the overall study, for the inpatient phase 
and for the outpatient phase over and for each co-administration category: 
 The number and percentage of subjects experiencing at least 1 TEAE by MedDRA 
preferred term and SOC. 
 The number and percentage of subjects experiencing an opioid withdrawal related 
TEAE as determined by the investigator by MedDRA preferred term and SOC. 
 The number and percentage of subjects experiencing a TEAE of special interest (Table 
2). 
 The number and percentage of subjects experiencing TEAEs by severity of event 
 The number and percentage of subjects experiencing treatment-related TEAEs (i.e. 
Possibly Related, Probably Related, Definitely Related) 
 The number and percentage of subjects experiencing at least 1 treatment emergent SAE 
by MedDRA preferred term and SOC  
 The number and percentage of subjects experiencing SAEs by severity of the event by 
MedDRA preferred term and SOC 
 The number and percentage of subjects experiencing SAEs by relatedness to IP 
Table 2: TEAEs of Special Interest 
Hypotension 
Rebound Hypertension 
Bradycardia 
dizziness 
agitation 
anxiety, nervousness 
chest pain, tightness in chest 
chest pain, tightness in chest 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 14


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 14 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
Table 2: TEAEs of Special Interest 
Hypotension 
Rebound Hypertension 
Bradycardia 
hypotension 
epistaxis 
confusion 
orthostatic hypotension 
fatigue 
flushing, warm feeling 
hypotension 
palpitations 
headache 
dizziness 
presyncope 
hypertension 
pallor 
syncope 
hypertensive encephalopathy 
lightheadedness 
nausea 
shortness of breath 
tachycardia 
pallor 
perspiration  
shortness of breath 
stroke/CVA 
syncope 
tachycardia 
tremor 
vision changes 
Narratives of deaths, serious and other significant AEs will be provided in the relevant section 
of the CSR. 
A complete subject listing of all AEs will be provided in Appendix 16.2 to the study report. 
This listing will include AE verbatim, MedDRA primary system organ class and preferred term, 
the time of onset and cessation of event relative to first dosing of study medication, duration of 
AE (for ongoing AEs use the date of investigator signature as the cessation date for calculation 
purposes), whether serious, severity, relationship to study medication, action taken and 
outcome. 
Treatment emergent and non-treatment emergent events will be listed separately. 
Vital Signs Measurements 
Summary statistics for observed and changes from baseline in sitting and standing vital signs, 
separately, will be tabulated at each follow-up for each vital sign parameter and at post-baseline 
endpoint for each variable overall and for each co-administration category. All values will be 
included in the summary of potentially clinically significant vital signs. However, post-baseline 
repeat/unscheduled assessments will be excluded for the other tabulations. 
In addition the number and proportion of subjects having PCS will be tabulated: 

Systolic blood pressure ≥180 mmHg and an increase of ≥ 20 mmHg from baseline

Systolic blood pressure ≤ 90 mmHg and a decrease ≥ 20 mmHg from baseline;

Diastolic blood pressure ≥ 105 mmHg and an increase ≥ 15 mmHg from baseline;
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 15


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 15 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 Diastolic blood pressure ≤ 50 mmHg and a decrease ≥ 15 mmHg from baseline; or 
Additionally, the number and proportion of subjects having a dose-hold due to a VS 
measurement will be tabulated as follows: 
Resting (sitting [or recumbent if necessary because of an AE]) 
 Systolic blood pressure <90 mmHg and >20% below screen value; 
 Diastolic blood pressure <50 mmHg and >20% below screen value; 
 Pulse <50 bpm and >20% below screen value; or 
 Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness). 
Orthostatic (after standing for 3 minutes) 
 Systolic blood pressure diastolic blood pressure, or pulse >25% below 
recumbent values. 
In addition, the number and proportion of subjects meeting the discontinuation Vital Signs 
criteria will be tabulated as follows: 
 Resting systolic blood pressure <70 mmHg; 
 Resting diastolic blood pressure <40 mmHg; 
 Resting pulse <40 bpm; 
 QTcF >500 msec or >25% above screen value for both males and females; or 
 Syncope. 
 Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or 
fluids). 
 Single occurrence of symptomatic bradycardia (as assessed by Principal 
Investigator/study physician/assigned staff, regardless of blood pressure) associated 
with chest pain, shortness of breath, or decreased level of consciousness. 
 Persistent hypertension – resting blood pressure ≥185/110 mmHg recorded on 3 
separate occasions taken at least 5 minutes apart AND within a 1-hour time period.  If 
2 of 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic 
≥110 mmHg) the subject must be discontinued. 
All of the above will be summarized overall and for each co-administration category at each 
study day.  
The incidence of missed standing vital signs will be counted for those subjects with a resting 
blood pressure measurement and a missing standing blood pressure measurement.  The count of 
unique subjects and number of events will be tabulated.  Consecutive missing measurements 
will be counted as one event.  Additionally, the number of missed doses and the reason for each 
missed dose will be presented for each subject and study day. 
The number and percentage of subjects with a reduced dose that still met each of the above 
criterion after the dose reduction will be presented overall and for each co-administration 
category by study day. 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 16


US WorldMeds, LLC 
Protocol USWM-LX1-3003-2 
Page 16 of 19 
Effective: 06-APR-2016 
PROPRIETARY AND CONFIDENTIAL 
Mean profiles by study day will be presented for sitting and standing blood pressure and pulse 
rate. 
ECG 
For ECG data collected during this study, a separate SAP will be used for the analysis and the 
results will be presented separately in a stand-alone report.   
In addition, PI overall interpretation of the ECG (Normal, Abnormal NCS, and Abnormal CS) 
will be listed in Appendix 16.2. 
Clinical Laboratory Evaluations 
Descriptive statistics will be calculated for the baseline values, study discontinuation values and 
for the changes from baseline for each continuous hematology, coagulation, chemistry and 
urinalysis parameter. Each measurement will be categorized as below, within, or above normal 
range, based on ranges supplied by the laboratory used. Shift tables in relation to the normal 
range from baseline to study discontinuation will be presented. For post-baseline laboratory 
values, only scheduled values will be tabulated.  Post-baseline repeat/unscheduled assessments 
will be disregarded, although they will be listed in the relevant appendices to the report; in 
particular all clinically significant values will be noted in a table or a separate listing. 
Details of clinically warranted clinical laboratory tests and microscopic urinalysis will be 
provided in Appendix 16.2 of the report.  
C-SSRS
The C-SSRS will be completed 3.5 hours after the first dose (8 AM) during in-clinic 
treatment, and once daily before an in-clinic dose of lofexidine during outpatient treatment, 
or, if applicable, at discontinuation from the study; 
The following will be summarized for the study overall and by inpatient or outpatient phase: 
1. To assess safety:
a.
Suicidality: The number and percentage of subjects reporting any suicidal
ideation or behavior throughout the assessment period.
b. Suicidal behavior only: The number and percentage of subjects reporting any
type of suicidal behavior throughout assessment period.
c.
Suicidal ideation only: The number and percentage of subjects reporting any
type of suicidal ideation throughout assessment period.
In addition, taking into account baseline data regarding suicidal ideation to determine if 
suicidal ideation or behavior has worsened: 
d. Emergence of suicidal ideation: The number and percentage of subjects
reporting no suicidal ideation at baseline and any type of ideation during the
assessment period.
e.
Emergence of serious suicidal ideation: The number and percentage of
subjects reporting no suicidal ideation at baseline and had serious suicidal
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 17


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 17 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
ideation (as defined above; score of 4 or 5 on suicidal ideation severity rating) 
during the assessment period.   
f. Worsening of suicidal ideation: The number and percentage of subjects whose 
most severe suicidal ideation rating is more severe than it was at baseline.  
g. Emergence of suicidal behavior: The number and percentage of subjects who 
had no suicidal behavior at baseline and any type of behavior during the 
assessment period.  
Physical Examination 
Complete physical examination will be assessed 3 to 4 hours after first dose on Day 1, as 
clinically warranted, and at discontinuation from the study. Each body system within the 
physical examination be summarized (Normal; Abnormal NCS, Abnormal CS) for each visit 
collected.  For body weight, descriptive statistics will be tabulated for baseline, end of study 
and the changes from baseline to end of the study. 
 
Concomitant medications 
Concomitant medication verbatim terms (as recorded on the CRFs) after the initial dose of 
study drug will be mapped to Anatomical Therapeutic Chemical (ATC) Level 2 and Drug 
Reference Names using the World Health Organization (WHO) dictionary (Version 6.15 
Enhanced) and tabulated overall. 
6.10 Change to Planned Protocol Analysis 
The following changes have been made to the planned protocol analyses sections: 
Section 6.10 Subject Cohorts 
Change: Addition of cohort for subjects undergoing methadone-assisted withdrawal. 
Reason: This cohort should have been included in the protocol. 
Section 6.10 Adverse Events 
Change: Addition of adverse event summaries by inpatient and outpatient phase. 
Reason: There is interest in the difference between inpatient and outpatient events. 
Section 6.10 Vital Signs Measurements 
Change: Addition of the incidence of missing standing vital signs measurements. 
Reason: There is interest in determining the number of subjects who could not stand. 
6.11 References 
(1) 
SAS Institute Inc.  The SAS System, Version 9.3.  Cary, NC, SAS Institute Inc. 2012. 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 18


 
 
US WorldMeds, LLC 
 
Protocol USWM-LX1-3003-2 
 
 
 
 
Page 18 of 19 
Effective: 06-APR-2016 
 
 
 
 
 
  
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
7. TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Table 
number 
Table Title 
8. FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
Figure 
number 
Figure Title 
9. APPENDIX 16.2 LISTINGS 
Listing 
number 
Listing Title  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 19


209229
uswm-lx1-3003-2-documentation-of-statistical-methods
 Pg. 20