Clinical trial NCT04070157
Conditions: Opioid Withdrawal (Disorder)
Keywords: Opioid Withdrawal Syndrome OWS Opioid taper Opioid withdrawal Opioid reduction Stopping opioids Opioid discontinuation non-opioid pain management
Sponsor: USWM, LLC (dba US WorldMeds)
Start date: 2019-08-02; Completion date: 2019-11-27
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Stopping prescription opioid pain medications can be difficult due to withdrawal symptoms. This study will test if LUCEMYRA helps reduce withdrawal symptoms and helps more people reduce their opioid dose compared to placebo.

Detailed description:
This randomized, double-blind, placebo-controlled pilot study will evaluate the safety and effectiveness of LUCEMYRA in the treatment of opioid withdrawal during an opioid taper in subjects with chronic non-cancer pain.

Subjects will begin a planned 14-day complete taper of their pre-study opioid medications and will be randomly assigned (1:1) to either LUCEMYRA or matching placebo. Study drug will be administered through the opioid taper and for 5 days after the opioid taper is completed. Study drug will then be tapered over a 4-day period for a total of approximately 21 days exposure to study drug.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Lofexidine intervention 2: Placebo
Intervention descriptions: intervention 1: Lofexidine 0.18 mg tablets. Dosing will begin with 1 tablet administered every 5-6 hours, up to 4 times day. The dose may be titrated but not to exceed 4 tablets 4 times a day. intervention 2: Matching placebo tablets. Dosing will begin with 1 tablet administered every 5-6 hours, up to 4 times day. The dose may be titrated but not to exceed 4 tablets 4 times a day.

Protocol documents:
ICF_001.pdf: 
PRODUCT: Lofexidine hydrochloride (HCl) tablets 
INFORMED CONSENT FORM 
PROTOCOL NUMBER / AMENDMENT: USWM-LX1-2010 / 1
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY 40241 
TITLE: 
A Randomized, Double-blind, Placebo-controlled Pilot Study to Evaluate the Safety and 
Effectiveness of LUCEMYRA in the Treatment of Opioid Withdrawal During an Opioid 
Taper in Subjects with Chronic Non-cancer Pain 
DOCUMENT DATE: Jul 3, 2019
IND NUMBER: 047857
NCT NUMBER: NCT04070157


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INFORMED CONSENT FORM AND AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
 
Sponsor / Study Title: 
  
US WorldMeds, LLC / “A Randomized, Double-blind, 
Placebo-controlled Pilot Study to Evaluate the Safety and 
Effectiveness of LUCEMYRA in the Treatment of Opioid 
Withdrawal During an Opioid Taper in Subjects with Chronic 
Non-cancer Pain” 
 
Protocol Number: 
 
USWM-LX1-2010 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
INTRODUCTION 
You are invited to take part in a research study. This research study is studying LUCEMYRA as a 
possible treatment for symptoms that may occur when you reduce over time your opioid pain 
medicine.  Another name for these symptoms is opioid withdrawal symptoms.   US WorldMeds, 
LLC is sponsoring this research study. 
 
Please read this form carefully. Take your time to ask the study doctor or study staff as many 
questions about the study as you would like. The study doctor or study staff can explain words 
or information that you do not understand. Reading this form and talking to the study doctor or 
study staff may help you decide whether to take part or not. If you decide to take part in this 
study, you must sign your name at the end of this form and date it.  
 
BACKGROUND AND PURPOSE  
You are being asked to participate in this research study because you take opioid medications 
for chronic non-cancer pain and you want to stop taking your opioid pain medications. Your 
reasons to stop taking your opioid pain medications may be because your opioid pain 
medication has caused problems which you can no longer put up with, such as anxiety, 
difficulty sleeping, constipation (having a hard time going to the bathroom), depression 
(unhappiness), foggy thinking, and issues at work or home. Having these problems with opioids 
is NOT a sign of addiction. 
 


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Stopping prescription opioid pain medications can be difficult due to withdrawal symptoms. 
Sometimes the fear of withdrawal symptoms can make you want to continue taking opioid pain 
medications, especially if you have tried but failed to stop or reduce your opioid dose (taper).  
 
The purpose of this research study is to study LUCEMYRA use in subjects who are tapering off 
their opioid prescription over a 2- to 3-week period. This study will:  
 
• test the safety and effectiveness of the study drug, LUCEMYRA. 
• test if LUCEMYRA helps reduce withdrawal symptoms. 
• test if LUCEMYRA helps more people reduce their opioid dose compared to placebo. 
 
LUCEMYRA is currently approved by the United States Food and Drug Administration (FDA) for 
the mitigation (lessening) of opioid withdrawal symptoms in patients stopping their opioid 
medication without a taper (meaning reduction over time). The taper used by some pain 
management physicians includes a much more gradual taper than what will be required in this 
study.  This may result in more severe withdrawal symptoms and may require more non-opioid 
pain treatment than would be experienced with a slower taper.  The use of LUCEMYRA in this 
study is investigational. An investigational use is one that is not approved by the United States 
FDA. The reason it is investigational is because LUCEMYRA has not been studied in subjects who 
are gradually tapering off their opioid medication. In this research study, LUCEMYRA will be 
compared to placebo. A placebo is designed to look like the study drug, but it contains no actual 
medicine. Neither you or the study center will know whether you are receiving LUCEMYRA or 
placebo. 
 
WHAT WILL HAPPEN DURING THE STUDY 
Your participation in this study (excluding the time spent for screening) will last about 51 days 
and will include about 6 study visits to the study center and about 4 phone calls with the study 
doctor or study staff. You will also receive reminders from time to time, either by a phone call, 
text, or email. There will also be a phone interview near the time of your End of Study Visit.  
 
During the study, you will take the study drug, and the study doctor will have you gradually 
reduce your dose of opioids over a 2- to 3-week period. The study doctor will work with you on 
managing any pain symptoms you may have during your opioid dose reduction. If you are 
having trouble reducing your opioids, the study doctor may have you pause your reduction or 
go back to your previous opioid dose. If this happens, you will be in the study for an extra week. 
 


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Screening: 
Before any study-related tests and procedures are performed, you will be asked to read, sign 
and date this form. The following screening tests and procedures will then be performed to 
determine if you qualify to take part in this study:  
 
• The study doctor may be someone different than your physician who prescribed your 
opioids. You will need to inform your pain physician of your plans to participate in this 
study. The study doctor will require a form signed by your pain physician confirming that 
they will resume your care after the study. 
• You and the study doctor will develop a plan for managing your pain and for reducing 
your opioid pain medications prior to you starting in the study. 
• You will be asked about your demographic information, medical history, current 
medications you are taking, current pain condition, and history of opioid pain 
medication use and withdrawal. You will have a short psychiatric evaluation to 
determine whether you are depressed or have suicidal thoughts.   
• You will have a complete physical examination, and your height and weight will be 
measured. 
• If you are a female, you will have a urine pregnancy test. 
• You will provide a urine sample, of approximately 2 tablespoons, to be used for routine 
safety laboratory tests. In addition, your urine will be tested to confirm you are taking 
the opioids you are prescribed, and it will check for other drugs such as marijuana or 
other illegal drugs and alcohol. 
• You will have approximately 1 tablespoon of blood drawn for routine safety laboratory 
tests.  
• Your vital signs will be measured, including blood pressure and pulse rate. 
• You will have an electrocardiogram. An electrocardiogram will measure the electrical 
activity of your heart. 
• You will be asked about any medications that you are currently taking. 
• You will complete a list of questions about your pain, current symptoms, and mental 
well-being on the computer or tablet. 
• You will receive instruction on how to complete an electronic medication diary to record 
information about your opioid medications, other medications, and the study drug while 
at home. 
• You will be trained on how to report your pain and withdrawal symptoms, take and 
record your vital signs, complete questions, and complete your electronic diary. 
 
Opioid Reduction (Taper) Plan: 
The study doctor will ask you questions to find out how much of your opioid medications you 
take each day. This will allow the study doctor to determine your taper plan. You will reduce 
your daily dose of opioids as close to 50% as possible during Week 1. During Week 2, your daily 
dose will be cut in half again. During Week 3, you will not be taking any opioids.   


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The study doctor may need to write you new opioid prescriptions, change the number of times 
in a day you take your opioid, or even prescribe a different opioid in order to taper. The sponsor 
will cover the cost of your opioid prescriptions while you are in the study. The study doctor will 
tell you when to fill your prescription, if needed, and when to start tapering your opioid. You 
must take only the pain medications prescribed by the study doctor while in the study.  The 
clinic will give you a schedule, so you will know the exact date when you are to taper your 
opioid medications and when phone calls and clinic visits will occur.  Here is an example of what 
your schedule will look like. 
 
 


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Up to 60 subjects will participate in this study at approximately 10 study centers. This study will 
use competitive enrollment. This means that when a target number of subjects begins the 
study, all further enrollment will be closed. Therefore, it is possible that you could be in the 
screening phase, ready to begin the study, and be discontinued without your consent if the 
target number of subjects has already begun the study. 
 
If you qualify to take part in this study and go on to receive study drug, then the following will 
happen:  
 
Study Drug:  
LUCEMYRA is a peach-colored tablet that contains 0.18 mg of lofexidine hydrochloride.  
 
You will be randomly assigned by chance (like the flip of a coin) to receive either LUCEMYRA or 
placebo (inactive substance that looks like LUCEMYRA). You will have a 50% (1 in 2) chance of 
receiving LUCEMYRA and a 50% (1 in 2) chance of receiving placebo. This is a double-blind 


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study, which means neither you nor the study doctor will know if you are taking LUCEMYRA or 
placebo. In case of an emergency, however, the study doctor can get this information. 
You will begin taking study drug after your dose of opioid pain medication has been reduced. 
You will be contacted to remind you how to decrease your dose of opioids. 
 
Your first dose of study drug will take place in the clinic. You will start by taking 1 tablet, by 
mouth, every 5 to 6 hours, up to 4 times each day. On the second day, you will take 2 tablets 
4 times each day, if you tolerated the previous dose. The study doctor will contact you on the 
second day to discuss adjusting your dose and to check on your well-being. The study doctor 
may increase or decrease your dose, depending on your symptoms. The maximum dose of 
study drug is 4 tablets, 4 times each day. At the end of the study, you will slowly reduce your 
dose of study drug, over 4 days, until you are no longer taking it. 
 
You will have the following study visits, reminder contacts, and phone calls, and undergo the 
following procedures. 
 
Visits 1, 2, 3, 4, 5, and End of Study 
The day before your first visit to the clinic, and your first dose of study drug, you will be 
contacted and instructed to reduce your last opioid dose of the day. The study doctor will 
instruct you on what dose to take. The next day, at Visit 1, you will take your first dose of study 
drug in the clinic. At Visit 1 and all other clinic visits, you will undergo the following tests or 
procedures unless otherwise indicated: 
 
• Brief physical examination 
• Short psychiatric exam, including any suicidal tendencies 
• Weight (End of Study Visit only) 
• Urine pregnancy test (End of Study Visit only) 
• Urine test for opioids, marijuana, other illegal drugs, and alcohol 
• Measurement of vital signs 
• Electrocardiogram 
• Medication diary review 
• Questionnaires about your symptoms and pain 
• Questions about how you are feeling and any changes with your medications 
• You will have approximately 0.5 tablespoons of blood drawn for routine safety 
laboratory tests (Visit 4 and End of Study Visit only). Although not noted as a risk in the 
label of LUCEMYRA, a small increase in laboratory tests that look at how your liver is 
working was seen in a few more patients that took LUCEMYRA over those who took 
placebo.  This means that during the study, laboratory tests that show how your liver is 
working will be performed at Visit 4 and end of study.  If any of your laboratory tests 
increase, your study doctor may require at least one additional blood draw to monitor 
your liver including a test for hepatitis.   Please inform your study doctor if you have 
been exposed to a hepatitis virus in the past. A positive hepatitis result from this test 


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will be reported to the local health department as required by state law. The results 
from this test are confidential, and the results will not be shared outside of this study 
except as required by state law.  Your study doctor will keep you informed of your 
laboratory test results. 
 
If you are having suicidal thoughts call the study doctor at the telephone number listed on the 
first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide Suicide Hotline 
that is answered 24 hours a day with a skilled, trained counselor. One example is the National 
Suicide Prevention Lifeline at 1-800-273-TALK (8255). 
 
Also, at Visit 1, the study center will train you on how to measure your vital signs. They will also 
provide you with a vital sign monitor and cuff for use in the study. At the end of the study, you 
will return the monitor. You may dispose of the cuff. 
 
If you have to pause your opioid dose reduction, you will have an extra study visit. 
 
Reminder Contacts 
The day before each scheduled opioid dose reduction, you will be contacted by phone, text, or 
other electronic message to remind you to reduce your opioid dose. You will also be contacted 
in the same way to remind you to begin tapering your dose of study drug. 
 
Phone Calls 1, 2, 3, and Follow-up 
While you are taking the study drug, you will have several phone calls with the study doctor or 
study staff to make sure that you are doing okay with your opioid dose reduction, to check on 
your overall well-being, and that you are tolerating the study drug. During these phone calls, 
you will be asked to do the following: 
 
• Measure your vital signs 
• Answer questions about how you are feeling 
 
If you have to pause your opioid dose reduction, you will have 1 extra phone call.  
 
There will be a follow-up phone call 30 days after your End of Study Visit. 
 
During the study, you are encouraged to contact the study doctor and the study center anytime 
questions or issues arise. 
 
Study Interview by phone 
During your End of Study Visit, the clinic staff will schedule a phone interview between you and 
a person hired by the sponsor (interviewer) to interview all study subjects in this study. This 
interview may occur at your End of Study Visit if it is convenient for you and the interviewer. 
The interview could take up to 1 hour of your time. If the interview cannot be scheduled during 


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your End of Study Visit, it will be arranged to occur within 5 days of your End of Study Visit. You 
will be given a phone number to call for the interview. You will only be identified by your study 
identification number. The interviewer will not know anything about you. They will not even 
know your name. The interview will be recorded and the interviewer will ask about your 
experience in the study. This information may be useful in planning future research studies with 
LUCEMYRA. 
 
Daily At-home Procedures 
As part of this study, you will be required to keep a study diary and record your answers to the 
questionnaires daily. You will also need to record when you take your doses of study drug and 
any other treatments you use during the study. For most of the study, the study doctor will 
record your vital signs taken during phone calls; however, during the time that you are tapering 
the study drug, you will need to record your vital signs in your study diary. While you are at 
home, you will need to complete the following in your study diary: 
 
• Answer questionnaires before bedtime; this will take no more than 10 minutes 
• Record study drug and other treatment use 
• Measure, and record in diary, vital signs twice a day (once in the morning and once in 
the evening) during reduction of study drug and through the end of the study 
 
After Study Treatment 
Because this is a research study, the study drug and your reduced opioid medications will be 
given to you only during this study and not after the study is over. 
 
EXPECTATIONS  
If you participate in this study, you will be expected to:  
• Attend each study visit 
• Complete all phone calls 
• Take the study drug as instructed 
• Taper your opioids as instructed 
• Manage your pain as discussed with the study doctor 
• Complete study diaries and questionnaires 
• Abstain from alcohol and other illicit substances 
• Bring with you at each visit your unused opioid medication and study drug.  
• Return the blood pressure monitor, unused opioid medication and study drug. You and 
the site staff will dispose of any unused opioid medication you have discontinued during 
that visit. 
 
 
 


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RISKS, SIDE EFFECTS, AND/OR DISCOMFORTS  
 
For LUCEMYRA: 
Likely 
• Insomnia (difficulty sleeping) 
• Orthostatic hypotension (low blood pressure upon standing up or sitting down) 
• Bradycardia (low heart rate) 
• Hypotension (low blood pressure) 
• Dizziness 
• Somnolence (drowsiness) 
• Sedation 
• Dry mouth 
 
Because of the risk of low blood pressure or slow heart rate, the study doctor will frequently 
monitor your vital signs, and you will be instructed to contact the clinic if you experience any 
signs or symptoms of low blood pressure or a slow heart rate. The study doctor will explain 
these signs and symptoms to you, show you how to measure your vital signs at home, how to 
recognize symptoms, and when to call the study center. 
 
Frequent 
• Syncope (fainting) 
• Tinnitus (ringing in the ears) 
 
Rare 
• Lethargy (sluggishness) 
• Constipation 
• Dysgeusia (distorted sense of taste) 
• Gastroesophageal reflux disease (flow of stomach acid up into the passageway between 
the mouth and the stomach) 
• Flatulence (gas) 
• Fatigue (tiredness) 
• Chest pain 
• Hypoacusis (hearing impairment) 
• Vertigo (dizziness) 
• Thoughts of suicide 
• Dry eye 
• Blurry vision 
• Decreased appetite 
• Fall 
• Hypersensitivity (allergic reaction) 
 


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RISKS OF STUDY PROCEDURES 
• Opioid dose reduction and discontinuation: 
o Opioid withdrawal: Sometimes when people reduce their dose of opioid 
medications, or stop taking them, they may experience opioid withdrawal. 
Possible symptoms of opioid withdrawal include nausea, vomiting, diarrhea, 
muscle pain/spasms/twitching, abdominal discomfort, sweating, runny nose, 
watery eyes, restlessness, tremors, chills, increased heart rate and blood 
pressure, and agitation. 
o Uncontrolled pain: Because you have been taking your opioid medications for 
your pain condition, as you decrease your dose or stop taking your opioids, your 
pain levels may change. You and the study doctor will develop a plan for 
managing pain prior to you starting in the study. 
o Reducing your opioids may also cause you to have mood changes such as 
sadness, anxiety or generalized feelings of stress. Please contact your study 
doctor if you are having a difficult time mentally with reducing your dose or 
handling symptoms of opioid withdrawal or pain. 
 
• Opioid use: After you complete this study, you will probably be more sensitive to the 
effects of opioids. Any opioid, even at doses you have taken in the past, could cause an 
overdose, severe medical problems, or even death. 
• Central nervous system depressants: Taking central nervous system depressants with 
LUCEMYRA may increase the risk of low blood pressure, fainting, and slow pulse. You 
should be cautious when driving or operating heavy machinery, until you know how you 
will react to LUCEMYRA. 
• Blood samples: Possible side effects from blood drawing include faintness, inflammation 
of the vein, pain, bruising, or bleeding at the site of puncture. There is also a slight 
possibility of infection. You will have a total of approximately 2 tablespoons of blood 
drawn during this study. 
• Electrocardiogram: Skin irritation is rare but could occur during an electrocardiogram 
from the electrodes or gel that is used. 
• Questionnaires: The questionnaires used in this study may be upsetting. You do not 
need to answer any questions that you are not comfortable with. 
 
If you are taking medicines which affect your central nervous system you must be on a stable 
dose for 30 days before starting the study, you must maintain that dose for the entire study. 
These medications include muscle relaxants, benzodiazepines (tranquilizers), hypnotics 
(medicines for sleep), soporifics (medicines for sleep), certain antidepressants, and selective 
serotonin reuptake inhibitors (a type of anti-depressant). Your study doctor will review your 
medications and tell you if you are taking any of these or other medications which must not be 
changed before or during the study.  
 


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During the study, you may develop new symptoms, unrelated to your opioid taper. Immediately 
report all new symptoms to your study doctor, even if they are symptoms you have had in the 
past but are now worse. 
 
If you receive placebo (the inactive substance) as part of this study, your symptoms of opioid 
withdrawal syndrome, may not improve or may get worse. It is important to let the study 
doctor know how you are feeling. 
 
UNFORESEEN RISKS  
Since the use of the study drug is investigational, there may be other risks that are unknown. 
Additionally, there may be unknown risks to a pregnancy, embryo, or fetus if you or your 
female partner become pregnant. 
 
BIRTH CONTROL RESTRICTIONS  
Taking the study drug may involve risks to a pregnant woman, an embryo, fetus (unborn baby), 
or nursing infant. Therefore, if you are pregnant, planning to become pregnant, planning to 
father a child, or are breastfeeding a child, you cannot participate in this study.   
 
Females: 
In order to reduce the risk of pregnancy, you should use an effective method of birth control 
while you are participating in this study and for 90 days after your last dose of the study drug. 
Acceptable methods of birth control for use in this study are oral contraceptives (birth control 
pills), patch, barrier method (diaphragm, sponge, or condom) with spermicide, intrauterine 
contraceptive systems (IUDs), levonorgestrel implant (Norplant™, Jadelle®, and others), 
medroxyprogesterone acetate contraceptive injection (Depo-Provera® and others), hormonal 
vaginal contraceptive ring, surgical sterilization of yourself or your partner, or complete 
abstinence from sexual intercourse. The study doctor or study staff will discuss this with you.  
 
If you become pregnant while you are participating in this study or within 30 days after you 
have stopped taking the study drug, tell your study doctor or study staff immediately. The study 
drug will be stopped and your participation in this study will be ended.  You will be asked to 
provide information about your pregnancy and the outcome.  
 
Males:  
In order to reduce the risk of pregnancy, you should use an effective method of birth control 
while you are participating in this study and for 90 days after your last dose of the study drug. 
Acceptable methods of birth control for use in this study are barrier method (diaphragm, 
sponge, or condom) with spermicide, surgical sterilization of yourself or your partner, or 
complete abstinence from sexual intercourse. The study doctor or study staff will discuss this 
with you.  
 


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If your female partner becomes pregnant while you are participating in this study or within 
30 days after you have stopped taking the study drug, tell your study doctor or study staff 
immediately.  
 
ALTERNATIVES TO PARTICIPATION  
This study is for research purposes only. The only alternative is to not participate in this study. 
 
NEW FINDINGS  
Any new important information that is discovered during the study and which may influence 
your willingness to continue participation in the study will be provided to you. 
 
BENEFITS 
You may benefit as a result of your participation in this study. There is, however, no guarantee 
that you will benefit from your participation in this study. Information learned from the study 
may help other people in the future.  
 
Ask the study doctor for your estimated recovery time from the study treatment or procedures 
done during your participation in this study. The effects of the study drug may be noticeable for 
a few days after you stop taking it which is one reason the study doctor would like to see you 
one week after you stop taking study drug.  They will also call you 30 days after your last dose 
of study drug to check on you. 
 
COMPENSATION FOR PARTICIPATION  
If you have any questions regarding your compensation for participation, please contact the 
study staff. 


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CONFIDENTIALITY   
Records of your participation in this study will be held confidential except when sharing the 
information is required by law or as described in this form. The study doctor, the sponsor or 
persons working on behalf of the sponsor, and under certain circumstances, the FDA and the 
Institutional Review Board (IRB) will be able to inspect and copy confidential study-related 
records which identify you by name. This means that absolute confidentiality cannot be 
guaranteed. If the results of this study are published or presented at meetings, you will not be 
identified. 
 
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. 
 
COMPENSATION FOR INJURY  
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are 
participating in this study. If you tell the study staff that you think you have been injured, they 
will help you get the care you need.  
 
If you are injured as a result of taking the study drug or from procedures done for the purpose 
of this study, the sponsor will pay for those medical expenses necessary to treat your injury that 
are not covered by your medical insurance or any other third-party coverage. You will not lose 
any of your legal rights or release the sponsor, the study doctor, the study staff, or study center 
from liability for mistakes by signing and dating this form. 
 
To pay medical expenses, related to your participation in the study, the sponsor will need to 
know some information about you like your name, date of birth, and Medicare Beneficiary 
Identifier. This is because the sponsor has to check to see if you receive Medicare and if you do, 
report the payment it makes to Medicare.  
 
COSTS  
There will be no charge to you for your participation in this study. The study drug, study-related 
procedures, and study visits will be provided at no charge to you or your insurance company. 
You will also be provided a pharmacy card to purchase your opioid prescription in the event 
your study doctor needs to prescribe a different opioid dose or opioid for your taper. Your 
study doctor will also tell you where you need to get your opioid prescription filled. 
 
 
 


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WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns, or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this form. If you seek emergency care, or 
hospitalization is required, alert the treating physician that you are participating in this research 
study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
 
 
. 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
Your decision to participate in this study is voluntary. You may choose to not participate or you 
may withdraw from the study for any reason, at any time, without penalty or loss of benefits to 
which you are otherwise entitled, and without any effect on your future medical care. However, 
please note that the FDA requires that any information collected up to the point of your 
withdrawal cannot be removed from the study. 
 
If you decide to stop participating, you will need to taper the study drug for 4 days, until you 
are no longer taking it, to avoid side effects. Stopping the study drug right away can cause 
severe side effects.  
 
The study doctor or the sponsor can stop your participation at any time without your consent 
for the following reasons: 
 
• If it appears to be medically harmful to you 
• If you fail to follow directions for participating in the study 
• If it is discovered that you do not meet the study requirements 
• If the study is canceled 
• For administrative reasons 
 


US WorldMeds, LLC / Protocol Number USWM-LX1-2010  
 
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Revised «PIApprovalDate» 
 
 
 
 
You will have some assessments done for safety at your last clinic visit. In addition, you will 
receive a follow-up phone call 30 days after your last dose of study drug. 
 
If you leave the study for any reason, the study doctor may ask you to have some end of study 
tests for your safety. If the study doctor is not your regular pain physician, your regular pain 
physician will be notified that you are finished being in the study and the study doctor will help 
you set up an appointment to occur as soon as possible.  If necessary, the study doctor will 
provide care for any residual pain you may have until your regular pain physician resumes your 
care.  Other information from the study may be shared so your regular pain physician can 
resume your care. 
 
PRIMARY HEALTH CARE PROVIDER NOTIFICATION OPTION 
I consent to having my family doctor or primary health care provider notified by the study 
center of my participation in this study and/or any significant findings related to my health 
(please check yes or no). 
 
YES (If yes, please complete the information below) 
 
NO 
  
Name and address of family 
doctor or primary health care 
provider: 
Name: 
Address: 
 
Telephone and Fax Number: 
Tel: 
Fax: 


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Revised «PIApprovalDate» 
 
 
 
 
CONSENT  
I have read and understand the information in this informed consent document. I have had an 
opportunity to ask questions and all of my questions have been answered to my satisfaction. I 
voluntarily agree to participate in this study until I decide otherwise. I do not give up any of my 
legal rights by signing and dating this consent document. I will receive a copy of this signed and 
dated consent document. 
 
 
________________________________________ 
 
 
Subject’s Printed Name  
 
 
________________________________________ 
 
___________  
Subject’s Signature 
 
 
 
 
 
Date 
 
 
________________________________________ 
 
 
Printed Name of the Person Conducting the  
 
 
Consent Discussion   
 
________________________________________ 
 
___________ 
Signature of the Person Conducting the  
 
 
Date 
 
Consent Discussion   
 
 
 
 
 
 
 
 
 
 


US WorldMeds, LLC / Protocol Number USWM-LX1-2010  
 
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Revised «PIApprovalDate» 
 
 
 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and research team will use and 
share health data about you to conduct the study. Health data may include: 
• Your name 
• Address 
• Phone number 
• Date of birth 
• Medical history 
• Information from your study visits, including all test results 
 
Health data may come from your study records or from existing records kept by 
your doctor or other health care workers.  
 
For this study, the research team may share health data about you with 
authorized users.  Authorized users may include: 
• Representatives of US WorldMeds which includes any person or company 
who is supporting US WorldMeds with this study 
• Representatives of 
 (an Institutional Review Board that reviews 
this study) 
• The FDA and other US federal and state agencies 
• Government agencies to whom certain diseases (like HIV, hepatitis, and 
STDs) must be reported 
• Governmental agencies of other countries 
• Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access 
your information to conduct this study 
• Other research doctors and medical centers participating in this research, if 
applicable 
• A data safety monitoring board which oversees this research, if applicable 
 


US WorldMeds, LLC / Protocol Number USWM-LX1-2010  
 
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«PiFullName» 
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Revised «PIApprovalDate» 
 
 
 
 
Your health data will be used to conduct and oversee the research, including for 
instance: 
 
• To see if the study drug works and is safe 
• To compare the study drug to other drugs 
• For other research activities related to the study drug 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways 
other than those listed here.  
 
Your permission to use and share health data about you will end in 50 years 
unless you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data about 
you at any time by writing to the study doctor at the address listed on the first 
page of this form. If you do this, you will not be able to stay in this study. No new 
health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may 
still be used and given to others as described in this form.  
 
Your right to access your health data in the study records will be suspended 
during the study to keep from changing the study results. When the study is over, 
you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in 
the study. 
 
 


US WorldMeds, LLC / Protocol Number USWM-LX1-2010  
 
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STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use, and share my 
health data as specified in this form. I will receive a signed and dated copy of this 
form for my records. I am not giving up any of my legal rights by signing and 
dating this form.  
 
__________________________________ 
Printed Name of Subject 
 
 
__________________________________ 
 
 
__________ 
Signature of Subject 
 
 
 
 
 
Date 
 
__________________________________ 
Printed Name of the Person Obtaining the  
Authorization 
 
 
__________________________________ 
 
 
__________ 
Signature of the Person Obtaining the 
 
 
Date 
Authorization 
 

Prot_SAP_002.pdf: 
PRODUCT: Lofexidine hydrochloride (HCl) tablets 
 
PROTOCOL NUMBER / AMENDMENT: USWM-LX1-2010  / 1 
 
 
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd. 
Louisville, KY 40241 
 
 
TITLE: 
A Randomized, Double-blind, Placebo-controlled Pilot Study to Evaluate the Safety and 
Effectiveness of LUCEMYRA in the Treatment of Opioid Withdrawal During an Opioid Taper 
in Subjects with Chronic Non-cancer Pain 
 
 
DOCUMENT DATE: 16 July 2019 
IND NUMBER: 047857 
NCT NUMBER: NCT04070157 


Protocol 
 
USWM-LX1-2010 Amendment 1 
1 
 
LUCEMYRA 
PROTOCOL USWM-LX1-2010 
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PILOT STUDY TO 
EVALUATE THE SAFETY AND EFFECTIVENESS OF 
LUCEMYRA IN THE TREATMENT OF OPIOID 
WITHDRAWAL DURING AN OPIOID TAPER IN 
SUBJECTS WITH CHRONIC NON-CANCER PAIN 
 
Protocol Number: 
USWM-LX1-2010 
Product: 
LUCEMYRA™ (lofexidine hydrochloride) 
Investigational New Drug # 
47,857 
Development Phase of Study: 
2 
Medical Monitor: 
 
Sponsor: 
US WorldMeds, LLC 
Original Protocol Date:  
15 May 2019 
Protocol Amendment 1 Date: 
16 July 2019 
 
 
 
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. 




Protocol 
 
USWM-LX1-2010 Amendment 1 
3 
 
1. 
STUDY CONTACTS 
Table 1: 
Study Contact Information 
Role in Study 
Name 
Address and Telephone Number 
Clinical Study Leader 
 
  
US WorldMeds, LLC 
4441 Springdale Road 
Louisville, KY 40241 
502-815-8131 
Responsible Physician 
 
Contract Medical Monitor 
 
 
 
Drug Safety/Serious 
Adverse Event Reporting 
(24-hour emergency contact) 
 
 will be notified of drug 
safety/serious events via email. 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
4 
 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
1. 
STUDY CONTACTS ...................................................................................................3 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................4 
TABLE OF CONTENTS .................................................................................................................4 
LIST OF TABLES ...........................................................................................................................9 
LIST OF FIGURES .......................................................................................................................10 
3. 
PROTOCOL SUMMARY ..........................................................................................11 
3.1. 
Synopsis ......................................................................................................................11 
3.2. 
Schema ........................................................................................................................20 
3.3. 
Schedule of Assessments ............................................................................................21 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................34 
5. 
INTRODUCTION ......................................................................................................36 
5.1. 
Background .................................................................................................................36 
5.1.1. 
Opioid Withdrawal Syndrome in Physically Dependent Patients with 
Chronic Pain ...............................................................................................................36 
5.1.2. 
LUCEMYRA™ (Lofexidine Hydrochloride) ............................................................39 
5.2. 
Study Rationale ...........................................................................................................39 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................41 
6.1. 
Primary Objective .......................................................................................................41 
6.2. 
Secondary Objectives .................................................................................................41 
6.3. 
Exploratory Objectives ...............................................................................................41 
6.4. 
Assessment Tools Used to Achieve Objectives ..........................................................41 
7. 
INVESTIGATIONAL PLAN .....................................................................................43 
7.1. 
Overall Study Design ..................................................................................................43 
7.2. 
Study Endpoints ..........................................................................................................45 
7.2.1. 
Safety Endpoints .........................................................................................................45 
7.2.2. 
Effectiveness Endpoints ..............................................................................................46 
7.2.3. 
Exploratory Endpoints ................................................................................................46 
7.3. 
Number of Subjects ....................................................................................................47 
7.4. 
Duration of Subject Participation ...............................................................................47 


Protocol 
 
USWM-LX1-2010 Amendment 1 
5 
 
7.5. 
Treatment Assignment ................................................................................................47 
7.6. 
Adjustment Criteria for Opioid Taper ........................................................................47 
7.7. 
Sponsor Criteria for Study Termination .....................................................................47 
8. 
SELECTION AND DISCONTINUATION OF SUBJECTS .....................................49 
8.1. 
Subject Inclusion Criteria ...........................................................................................49 
8.2. 
Subject Exclusion Criteria ..........................................................................................50 
8.3. 
Screen Failures ............................................................................................................52 
8.4. 
Lifestyle Considerations .............................................................................................52 
8.5. 
Subject Discontinuation Criteria .................................................................................52 
8.6. 
Early Discontinuation Visit ........................................................................................53 
8.6.1. 
Early Discontinuation Follow-up ...............................................................................54 
9. 
TREATMENT OF SUBJECTS ..................................................................................55 
9.1. 
Randomization and Blinding ......................................................................................55 
9.1.1. 
Randomization ............................................................................................................55 
9.1.2. 
Maintaining and Breaking the Blind ...........................................................................55 
9.2. 
Treatments Administered ............................................................................................55 
9.2.1. 
Multimodal Pain Management Plan ...........................................................................55 
9.2.2. 
Study Drug Preparation ..............................................................................................56 
9.2.3. 
Study Drug Administration.........................................................................................56 
9.3. 
Adjustment Criteria for Opioid Taper ........................................................................57 
9.4. 
Prior and Concomitant Treatments .............................................................................59 
9.4.1. 
Prohibited Treatments .................................................................................................59 
9.4.2. 
Permitted Treatments ..................................................................................................59 
9.5. 
Treatment Compliance ................................................................................................61 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................62 
10.1. 
Study Drug ..................................................................................................................62 
10.1.1. 
Lofexidine Hydrochloride ..........................................................................................62 
10.1.2. 
Placebo ........................................................................................................................62 
10.2. 
Study Drug Packaging and Labeling ..........................................................................63 
10.3. 
Study Drug Storage .....................................................................................................63 
10.4. 
Study Drug Preparation ..............................................................................................63 
10.5. 
Administration ............................................................................................................63 
10.6. 
Study Drug Accountability .........................................................................................63 


Protocol 
 
USWM-LX1-2010 Amendment 1 
6 
 
10.7. 
Study Drug Handling and Disposal ............................................................................63 
11. 
ASSESSMENTS OF EFFECTIVENESS...................................................................64 
11.1. 
Numeric Rating Scale (NRS) of Pain Intensity ..........................................................64 
11.2. 
Clinical Opiate Withdrawal Scale (COWS) ...............................................................64 
11.3. 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) .....................................64 
11.4. 
Subjective Opiate Withdrawal Scale of Handelsman (SOWS-H) ..............................65 
11.5. 
Hospital Anxiety and Depression Scale (HADS) .......................................................65 
11.6. 
Insomnia Severity Index (ISI) ....................................................................................66 
11.7. 
Modified Clinical Global Impression – Subject Version (MCGI-S) ..........................66 
11.8. 
Modified Clinical Global Impression – Rater Version (MCGI-R) .............................66 
11.9. 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) ..............................................................66 
11.10. 
Short Form Health Survey – 36 Items (SF-36) ...........................................................67 
11.11. 
Subject Satisfaction Questionnaire .............................................................................67 
11.12. 
Subject Interview ........................................................................................................67 
12. 
ASSESSMENTS OF SAFETY ..................................................................................68 
12.1. 
Safety Parameters .......................................................................................................68 
12.1.1. 
Demographic/Medical History ...................................................................................68 
12.1.2. 
Vital Signs ..................................................................................................................68 
12.1.3. 
Weight and Height ......................................................................................................69 
12.1.4. 
Physical Examination .................................................................................................69 
12.1.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................69 
12.1.6. 
Electrocardiogram .......................................................................................................70 
12.1.7. 
Laboratory Assessments .............................................................................................70 
12.1.7.1. 
Evaluation of Treatment-emergent Elevated Liver Function Tests ............................72 
12.2. 
Adverse and Serious Adverse Events .........................................................................73 
12.2.1. 
Definition of Adverse Events .....................................................................................73 
12.2.1.1. 
Adverse Event .............................................................................................................73 
12.2.1.2. 
Serious Adverse Event ................................................................................................74 
12.2.2. 
Relationship of Adverse Event to Study Drug ...........................................................75 
12.2.3. 
Recording Adverse Events .........................................................................................76 
12.2.4. 
Follow-up of Adverse Events .....................................................................................76 
12.2.5. 
Expedited Reporting of Events ...................................................................................77 
12.2.5.1. 
Events Requiring Expedited Reporting to 
 ....................................................77 


Protocol 
 
USWM-LX1-2010 Amendment 1 
7 
 
12.2.5.2. 
Timeframe for Collecting and Reporting Serious Adverse Events and Other 
Immediately Reportable Events ..................................................................................77 
12.2.5.3. 
Regulatory Notification ..............................................................................................77 
12.2.6. 
Pregnancy ...................................................................................................................77 
13. 
STATISTICS ..............................................................................................................78 
13.1. 
General Statistical Considerations ..............................................................................78 
13.2. 
Sample Size Determination ........................................................................................78 
13.3. 
Analysis Populations ..................................................................................................79 
13.4. 
Statistical Analyses .....................................................................................................79 
13.4.1. 
Effectiveness Analyses ...............................................................................................79 
13.4.1.1. 
Successful Completion of Opioid Taper .....................................................................79 
13.4.1.2. 
COWS, SOWS-Gossop, and SOWS-H ......................................................................79 
13.4.1.3. 
MCGI-R and MCGI-S ................................................................................................79 
13.4.1.4. 
Time to Study Drug Discontinuation ..........................................................................79 
13.4.1.5. 
Numerical Rating Scale ..............................................................................................80 
13.4.1.6. 
ISI, HADS, EQ-5D-5L, and SF-36 .............................................................................80 
13.4.1.7. 
Daily Dose of Opioids and Number of Non-Opioid Concomitant 
Medications for Withdrawal Symptoms .....................................................................82 
13.4.2. 
Safety Analysis ...........................................................................................................82 
13.5. 
Interim Analysis ..........................................................................................................83 
14. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................84 
14.1. 
Regulatory and Ethical Considerations ......................................................................84 
14.2. 
Informed Consent .......................................................................................................84 
14.3. 
Source Documents and Retention ...............................................................................85 
14.4. 
Subject Confidentiality ...............................................................................................86 
14.5. 
Study Monitoring and Data Quality ...........................................................................86 
14.6. 
Audits and Inspections ................................................................................................87 
14.7. 
Publication Policy .......................................................................................................87 
15. 
LIST OF REFERENCES ............................................................................................88 
16. 
APPENDICES ............................................................................................................91 
16.1. 
Numeric Rating Scale of Pain Intensity ......................................................................91 
16.2. 
Baseline Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................92 


Protocol 
 
USWM-LX1-2010 Amendment 1 
8 
 
16.3. 
Columbia-Suicide Severity Rating Scale (C-SSRS)–Since Last Visit .......................94 
16.4. 
Clinical Opiate Withdrawal Scale (COWS) ...............................................................96 
16.5. 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) .....................................97 
16.6. 
Subjective Opiate Withdrawal Scale of Handelsman (SOWS-H) ..............................98 
16.7. 
Hospital Anxiety and Depression Scale (HADS) .......................................................99 
16.8. 
Insomnia Severity Index (ISI) ..................................................................................100 
16.9. 
Modified Clinical Global Impression – Subject Version (MCGI-S) ........................101 
16.10. 
Modified Clinical Global Impression – Rater Version (MCGI-R) ...........................102 
16.11. 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) ............................................................103 
16.12. 
Short Form Health Survey – 36 Items (SF-36) .........................................................105 
16.13. 
Subject Satisfaction Questionnaire ...........................................................................111 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
9 
 
LIST OF TABLES 
Table 1: 
Study Contact Information ...........................................................................................3 
Table 2: 
Schedule of Assessments Performed at the Clinic and Phone Calls: Standard 
Study Schedule ...........................................................................................................22 
Table 3: 
Schedule of Assessments Performed at the Clinic and Phone Calls: Study 
Schedule with Opioid Taper Pause .............................................................................27 
Table 4: 
Schedule of Assessments Performed at Home: Standard Study Schedule .................32 
Table 5: 
Schedule of Assessments Performed at Home: Study Schedule with Opioid 
Taper Pause .................................................................................................................33 
Table 6: 
List of Abbreviations ..................................................................................................34 
Table 7: 
Assessment Tools Used to Achieve Objectives ..........................................................42 
Table 8: 
Investigational Product ...............................................................................................62 
Table 9: 
SOWS-Gossop Scoring Method .................................................................................65 
Table 10: Clinical Laboratory Tests ...........................................................................................71 
Table 11: Definition of Serious Adverse Event ..........................................................................75 
Table 12: Analysis Populations ..................................................................................................79 
Table 13: Recoding Items for the Short Form Health Survey ....................................................81 
Table 14: Definition of Average Scale Scores for Short Form Health Survey ...........................81 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
10 
 
LIST OF FIGURES 
Figure 1: 
Opioid Taper ...............................................................................................................20 
Figure 2: 
Width of 95% Confidence Interval as a Function of Sample Size .............................78 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
11 
 
3. 
PROTOCOL SUMMARY 
3.1. 
Synopsis  
Name of Sponsor/Company: US WorldMeds, LLC 
Name of Investigational Product: Lofexidine hydrochloride (HCl) (LUCEMYRA™) 
Name of Active Ingredient: Lofexidine 
Title of Study: A Randomized, Double-Blind, Placebo-Controlled Pilot Study to Evaluate the Safety 
and Effectiveness of LUCEMYRA in the Treatment of Opioid Withdrawal During an Opioid Taper in 
Subjects with Chronic Non-Cancer Pain 
Study Center(s): 7 
Studied Period (years):  
Estimated date first subject enrolled: July 2019 
Estimated date last subject completed: December 2019 
Phase of Development: 2 
 
Objectives and Assessments:  
Objectives 
Endpoints 
Primary 
 
• 
Evaluate the safety and tolerability of 
LUCEMYRA versus placebo when used 
during an opioid taper in subjects with 
chronic non-cancer pain 
AE reports, clinical laboratory assessments, 
monitoring of DILI, vital signs, C-SSRS 
Secondary 
 
• 
Estimate the difference between 
treatment groups in measures related to 
opioid withdrawal and completion of 
opioid discontinuation when tapered 
• 
Estimate the difference between 
treatment groups in measures of 
effectiveness in pain relief, quality of 
life, and treatment satisfaction 
Taper completion status, reduction in opioid 
use, urine drug screen, COWS, MCGI-R, 
MCGI-S, SOWS-Gossop, SOWS-H 
 
EQ-5D-5L, HADS, ISI, NRS, SF-36, Subject 
Satisfaction, and use of rescue medication for 
pain 
AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; 
DILI = drug-induced liver injury; EQ-5D-5L = EuroQol 5-Dimension 5-Level; HADS = Hospital Anxiety and Depression 
Scale; ISI = Insomnia Severity Index; MCGI-R = Modified Clinical Global Impression – Rater Version; 
MCGI-S = Modified Clinical Global Impression – Subject Version; NRS = Numeric Rating Scale; SF-36 = Short Form 
Health Survey– 36 items; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; SOWS-H = Subjective Opiate 
Withdrawal Scale of Handelsman 
Rationale: A significant portion of the public health issues related to long-term prescription opioid 
use are thought to arise from the difficulty of opioid discontinuation. Following the approval of 
LUCEMYRA for mitigation of opioid withdrawal symptoms to facilitate abrupt opioid 
discontinuation in adults, its use in the setting of an opioid taper has become a topic of interest among 
clinicians managing physical opioid dependence in chronic pain patients.  
Enhanced treatment options for emerging opioid withdrawal symptoms during opioid taper regimens 
may permit development of more efficient tapering protocols, which in turn would have significant 


Protocol 
 
USWM-LX1-2010 Amendment 1 
12 
 
impact on reducing risk to patients on chronic opioids and may positively impact health economic 
outcomes.  
There is a notable lack of well-controlled data on the opioid withdrawal syndrome during an opioid 
taper in chronic non-cancer pain patients. Gradually tapering a patient’s opioid dose with small 
reductions in dose over a prolonged period of time is a practice inherently designed to mitigate the 
potential for opioid withdrawal. LUCEMYRA’s effectiveness in treating opioid withdrawal 
symptoms has been established in the setting of abrupt opioid discontinuation; however, has not been 
thoroughly evaluated in the setting of an opioid taper. Opioid tapers are often conducted over several 
weeks, if not months, resulting in the potential for at least cumulative use of LUCEMYRA for beyond 
14 days. A clinical trial is necessary to assess for a signal of serious hypotension, bradycardia, 
syncope, hepatotoxicity, or rebound hypertension, or identify potential unexpected serious risks of 
long-term use of LUCEMYRA in the setting of an opioid taper as the majority of the existing safety 
data for LUCEMYRA is on less than 14 days of use. This pilot study is intended to inform critical 
study design elements for a future pivotal study to assess the safety and efficacy of LUCEMYRA for 
use beyond 14 days in the setting of an opioid taper. 
Methodology:  
This is a pilot, multicenter, randomized, double-blind, placebo-controlled, outpatient clinical trial to 
assess the safety and tolerability, and to estimate the effectiveness of LUCEMYRA for mitigating the 
symptoms of opioid withdrawal in the setting of an opioid taper in subjects with chronic non-cancer 
pain. 
After a Screening period of up to 28 days, subjects will begin a planned 14-day complete taper of 
their pre-study opioid and will be randomly assigned (1:1) to either LUCEMYRA or matching 
placebo. Study drug will be administered through the opioid taper and for 5 days after the opioid taper 
is completed. Study drug will then be tapered over a 4-day period for a total of approximately 21 days 
exposure to study drug (Figure 1). 
Day 1 dosing with study drug will begin in the clinic as 1 tablet (LUCEMYRA 0.18 mg/tablet or 
matching placebo) 4 times per day (QID) for a total daily dose of LUCEMYRA 0.72 mg or matching 
placebo. Subjects will be instructed to take their study drug in the morning upon awakening and then 
every 5 to 6 hours thereafter. Doses should be taken 5 to 6 hours apart and no more than 4 times per 
day. At the Day 1 Visit (Visit 1), the Investigator should schedule a phone call with the subject, to 
occur prior to the second dose of study drug on Day 2, to review the subject’s at-home vital signs 
measurement and how the subject is feeling. The subject will be instructed to contact the site if they 
experience signs or symptoms of hypotension, bradycardia, or orthostasis (eg, lightheadedness, slow 
heart rate, dizziness, feeling faint at rest or when standing up) while continuing to dose at home on 
Day 1. If the subject contacts the site on Day 1 reporting these symptoms, the Investigator should 
consider reducing the planned first daily dose on Day 2. 
On Day 2 the subject will be instructed to take 2 tablets QID (LUCEMYRA 1.44 mg/day or matching 
placebo), unless Day 1 dosing was not well-tolerated. The subject should contact the site if they 
experience signs or symptoms of hypotension, bradycardia, or orthostasis (eg, lightheadedness, slow 
heart rate, dizziness, feeling faint at rest or when standing up) after the first daily dose. The 
Investigator will contact the subject on Day 2, prior to the second dose of the day, to review the 
subject’s at-home vital signs measurement and how the subject is feeling. The Investigator should 
discuss with the subject any changes to dosing of study drug. Dosing instructions may include an 
increase to 3 tablets per dose due to subject report of intolerable opioid withdrawal symptoms, or a 
reduction back to 1 tablet per dose, due to intolerability of study drug. 
On Day 3 and beyond, dosing will be at the discretion of the Investigator, as guided by subject 
tolerability of study drug and opioid withdrawal symptoms. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
13 
 
The dose of study drug may be increased to manage opioid withdrawal symptoms. If an increased 
dose of study drug is not well tolerated, the dose can be decreased. A single dose of study drug should 
not exceed 4 tablets (LUCEMYRA 0.72 mg or matching placebo). The total daily dose of study drug 
should not exceed 4 tablets QID (LUCEMYRA 2.88 mg/day or matching placebo). 
Subjects will be tapered from their baseline total daily dose of opioid (calculated as morphine 
equivalent dose [MED]) over a 14-day period. The opioid dose will be decreased as close as possible 
to achieve the following dose reduction targets: 50% from the baseline MED beginning with the last 
dose of the day on Day -1, an additional 25% of the baseline MED beginning on Day 6, and a final 
25% of the baseline MED (to dose of zero) beginning on Day 13. Reminders for opioid dose 
reduction may be done via phone, text, or other electronic message. 
Opioid dosing to achieve the required dose reductions in accordance with the protocol defined taper 
must be planned during Screening. Any changes in opioid prescription to facilitate the protocol taper 
should be discussed with the subject’s primary pain physician, when applicable, and prescribed in 
advance of randomization. The Investigator should work with a preferred pharmacy informed about 
the subject’s participation in a clinical trial in order to fulfill prescribing needs to facilitate the opioid 
taper. Opioid prescriptions should be written to accommodate the planned taper, as specified per 
protocol in Section 9.3. The subject’s baseline opioid regimen and MED calculation as well as the 
opioid regimen planned to achieve each taper step should be submitted to and approved by the 
Medical Monitor prior to Day -1. 
Non-opioid medications taken during the study should be in compliance with the allowed 
concomitant treatments in Section 9.4. Opioid dose reductions may not occur on a Friday or Saturday 
unless clinic can accommodate subjects on Saturday and Sunday. Qualified study personnel at the 
clinic should call the subject the day after the opioid dose is decreased (except on Day 1 since the 
subject will come to the clinic) to review the subject’s at-home vital signs measurement and how the 
subject is feeling. Upon review by the Investigator or designee, changes to dosing of study drug 
should also be discussed with the subject if applicable. 
Subjects who experience intolerable withdrawal symptoms, despite increasing their dose of study 
drug to the maximum tolerated dose (not to exceed 4 tablets QID), will be allowed to pause the opioid 
taper once. Pausing the opioid taper includes either a return to the last stable opioid dose for the 
remainder of the current opioid dose reduction period, or remaining on the current opioid dose instead 
of reducing at the next scheduled reduction, resulting in an overall extended opioid taper period and 
study duration. For example, if a subject experiences intolerable withdrawal at the second opioid dose 
reduction step [25% of baseline MED], they may either 1) return to the first reduction dose [50% of 
baseline MED]) or, 2) when the withdrawal persists until the next scheduled reduction step, they may 
remain for longer at the current opioid dose [25% of baseline MED]. In both cases, the taper must be 
resumed following the single pause in accordance with the protocol schedule. Subjects who cannot or 
are unwilling to continue the opioid taper after one pause will be discontinued from the study. 
Decisions on whether to pause the opioid taper will be based on subject request and an evaluation (in 
clinic or over the phone) of the subject’s status by the Investigator. Subjects may request to pause the 
opioid taper due to opioid withdrawal symptoms. If the subject’s last COWS score is ≥5 OR if based 
on i) the Investigator’s discussion with the subject, ii) review of ongoing subject-reported withdrawal 
related AEs, and iii) most recent scores for subject reported withdrawal scales, the subject’s desire to 
pause the taper is related primarily to opioid withdrawal discomfort in the Investigator’s opinion, then 
the taper may be paused. In the event that the Investigator assesses the subject’s desire to pause the 
taper to be primarily related to pain, a taper pause will not be permitted; however, if the subject is 
willing to continue the per protocol taper, recommended modifications to their concurrent pain 
management plan should be discussed and recorded. Subjects unwilling to continue the per protocol 
taper and not experiencing opioid withdrawal to permit a single pause should be discontinued from 
the study. 


Protocol 
 
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Study drug dosing for an opioid taper pause will remain at the discretion of the Investigator, as guided 
by subject tolerability of study drug and opioid withdrawal symptoms. The dose of study drug can be 
increased or decreased as needed. 
Dosing of study drug will continue for 5 days after the last opioid dose. Study drug will then be 
tapered over an additional 4 days (Section 9.2.3). 
Subjects will be given a diary to take home and will use it to complete daily questionnaires regarding 
withdrawal and other symptoms, average and worst daily pain, record opioid and study drug 
administration and concomitant treatment use (including use of medication for pain or opioid 
withdrawal symptoms). 
Subjects will take their blood pressure and heart rate at home using a vital sign monitor. At home 
readings will be collected during phone calls conducted by study staff after each opioid dose 
reduction and twice daily (morning and evening) during the 4-day study drug taper through the End of 
Study (EOS) Visit. Subjects will record readings in their diary.  
Subjects will return to the clinic on Day 3, Day 8, and then on a weekly basis following 
randomization during study drug administration for assessments. With the exception of Day 1 
(Visit 1), clinic visits can occur ± 1 day from the study-specified timepoint. Subjects will return to the 
clinic approximately 7 days after their last dose of study drug. At 30 days following the last dose of 
study drug, subjects will receive a telephone call for a safety follow-up and assessment of the 
subject’s current opioid usage, after which their participation in the study will be complete. 
Subjects who prematurely discontinue the study will be instructed to taper study drug as described in 
Section 9.2.3 and to complete the at-home assessments for the study drug taper period (Table 4 or 
Table 5). Once discontinued, subjects may not re-enter the study. 
Number of Subjects:   
60 subjects (30 LUCEMYRA, 30 placebo) 
A sample size of 30 subjects per group provides adequate precision for the estimated treatment 
difference for the incidence of adverse withdrawal events during opioid taper. Precision of the 
estimated difference is quantified by the width of the 95% confidence interval for the treatment 
difference. 
Diagnosis and Main Criteria for Eligibility:  
Inclusion Criteria 
1. Subject can provide written informed consent. 
2. Subject is willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
3. Chronic non-cancer pain diagnosis such as low back pain, chronic neck pain, osteoarthritis, 
and prolonged post-surgical pain with daily pain for a minimum of 6 months. 
4. Men and women at least 18 years of age at the time of signing informed consent. 
5. Self-reported use of prescribed oral opioid medication(s), taken as tablets, pills, or capsules, 
of at least 50 morphine mg equivalent (MME) but no higher than 240 mg MME daily or near 
daily (≥5 days per week) for at least 12 weeks and seeking to discontinue their opioid 
medication. MMEs must be calculated using conversion factors recommended by the Center 
for Disease Control and Prevention to confirm the MED for the day is between 50-240 MME, 
including both breakthrough and around-the-clock pain medications, at Screening. The 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Medical Monitor must review and approval all baseline opioid use consumption and planned 
taper dosing regimens prior to Day -1.  
6. Willing to be treated with non-opioid treatments for pain (in addition to opioid being tapered) 
for the duration of the study. 
7. Subject agrees to follow the opioid taper plan, both in terms of the planned changes in the 
doses of opioid medications and the schedule for when opioid dose reductions will be made, 
as outlined by the Investigator and approved by the study Medical Monitor.   
8. Subject agrees to partner with his or her pain physician on a subject-centered pain 
management program during the study. 
9. If the subject is not normally a patient at the clinic, the subject’s normal pain physician must 
sign an attestation that the physician agrees to resume the subject’s pain management care 
following the study. 
10. In generally good health, in the opinion of the Investigator, other than the underlying chronic 
pain syndrome at Screening based upon the results of a medical history, physical 
examination, 12-lead electrocardiogram, and laboratory profile. 
11. Subject agrees to abstain from use of alcohol during the study. 
12. Women of childbearing potential must have a negative pregnancy test at Screening. 
13. Non-pregnant, non-lactating women who are postmenopausal, naturally or surgically sterile, 
or who agree to use acceptable contraceptive methods throughout the course of the study. 
Postmenopausal is defined as at least 12 months of amenorrhea, or at least 6 weeks following 
surgical menopause, defined as bilateral oophorectomy, tubal ligation, or hysterectomy. If of 
childbearing potential, subject must have been using birth control for at least 30 days and 
must agree to use one of the following methods of birth control: 
• 
Oral contraceptives 
• 
Patch 
• 
Barrier method (diaphragm, sponge, or condom) with spermicidal preparations 
• 
Intrauterine contraceptive system 
• 
Levonorgestrel implant 
• 
Medroxyprogesterone acetate contraceptive injection 
• 
Complete abstinence from sexual intercourse 
• 
Hormonal vaginal contraceptive ring; surgical sterilization, or partner sterile 
14. If male, must agree to use one of the birth control methods listed in inclusion criterion 13 
throughout the entire study period and for 90 days after the last dose of study drug. Must not 
donate sperm for 90 days after the last dose of study drug. 
15. Able to speak, write, and understand English, understand the consent form, and be able to 
effectively communicate with the study staff. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Exclusion Criteria 
1. Has a primary diagnosis of complex regional pain syndrome, central neuropathic pain, 
somatoform pain syndromes, acute nerve root compression, any acute or progressive 
infectious, inflammatory, or neurological process. 
2. Liver disease that requires medication or medical treatment, and/or aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 3 times the 
upper limit of normal (ULN). 
3. Gastrointestinal or renal disease, which would significantly impair absorption, metabolism or 
excretion of study drug, or would require medication or medical treatment. 
4. Has a diagnosis of epilepsy or history of seizures. 
5. Has clinically significant abnormal laboratory value(s). 
6. Self-reported or evidence of opioid use disorder (OUD) or other substance use disorder 
within last 12 months prior to Screening using the Sponsor-provided Mini-International 
Neuropsychiatric Interview. 
7. Urine toxicology screen positive for any illicit or non-prescribed opioid drugs prior to 
randomization. 
8. Taking prescription methadone, buprenorphine, fentanyl rapid acting products, tapentadol, 
tramadol, butorphanol, meperidine, or levorphanol for any reason. 
9. Known or suspected pregnancy, planned pregnancy, or lactation. 
10. Any of the following cardiovascular abnormalities at Screening and before randomization: 
a. Resting heart rate ≥105 bpm or <55 bpm or symptomatic bradycardia; 
b. Resting systolic blood pressure ≥160 mmHg or <95 mmHg or symptomatic hypotension; 
c. Resting diastolic blood pressure ≥90 mmHg or <65 mmHg; 
d. Clinically significant abnormal electrocardiogram (eg, second- or third-degree heart 
block, uncontrolled arrhythmia; QT corrected by heart rate by Fridericia's method (QTcF) 
of ≥450 msec or a history of QT interval prolongation; 
e. New York Heart Association class III or IV; or 
f. History of myocardial infarction within 6 months of Screening. 
Medications taken for stable hypertension are permitted when dose/regimen has been 
consistent for a minimum of 3 month prior to screening. 
11. Any severe or unstable psychiatric disorder including post-traumatic stress disorder, 
schizophrenia, bipolar disorder, major depression, substance abuse, or suicidality as 
determined by the Investigator. 
12. Subject answers “yes” to “suicidal ideation” in prior 24 months to any items 1 through 5 on 
the C-SSRS, or subject answers “yes” to any lifetime “suicidal behavior” item on the 
C-SSRS. 
13. Requires any of the following medications currently or within the past 30 days: 
a. Alpha-2 adrenergic agonists 
b. Antiarrhythmics 
c. Barbiturates 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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d. Paraldehyde 
e. Stiripentol 
f. Psychoactive herbal preparations (including St. John’s Wort, Kratom, cannabis, and 
products containing cannabinoids) 
g. Aspirin (baby aspirin permitted if taking prior to study for cardioprotective purposes) 
14. Medications given for stable neuro-psychiatric diagnoses must be at a consistent 
dose/regimen for at least 30 days prior to randomization. Central nervous system (CNS) 
depressants in combination with lofexidine may increase the risk of hypotension and 
bradycardia. Acceptable regular, stable-dosing medications within this category include:   
a. Strong cytochrome P450-2D6 inhibitors, muscle relaxants, benzodiazepines, hypnotics, 
soporifics, tricyclic antidepressants, selective serotonin reuptake inhibitors, permitted 
anticonvulsants (including but not limited to gabapentin and pregabalin) must be taken at 
doses within the ranges recommended per product labeling. 
b. Subject must meet all other eligibility criteria while at the established stable dose/regimen 
and the medication must be continued at the same dose/regimen for the duration of the 
study drug administration period.  
c. If taken on an as needed basis, subjects should discontinue medications in these 
categories 2 weeks prior to randomization and avoid use for the duration of the study 
drug administration period. 
d. No more than 1 drug in each class should be part of the stable regimen (eg, subjects 
taking 2 permitted muscle relaxants, 2 anticonvulsants, 2 hypnotics, or 2 soporifics 
should be excluded until they are taking no more than 1 drug in each class). 
15. Treatment with an investigational drug, device, or biological agent within 30 days before 
Screening or while participating in this study. 
16. Any anticipated or scheduled surgery during the study period. 
17. Major surgery within 30 days before Screening. 
18. Metastatic cancer diagnosed within the previous year or diagnosis of any malignancy or 
neoplasm within 3 months prior to Screening, exclusive of basal cell carcinoma.  
19. Has self-reported acquired immunodeficiency syndrome or self-reported human 
immunodeficiency virus positive status.  
20. History of lack of tolerance or lack of response to LUCEMYRA which, in the Investigator’s 
opinion, makes the subject a poor candidate for the study. 
Study Drug Dosage and Mode of Administration:  
LUCEMYRA 0.18-mg tablets or placebo taken orally. A single dose of study drug should not exceed 
4 tablets (LUCEMYRA 0.72 mg or matching placebo). The total daily dose of study drug should not 
exceed 4 tablets QID (LUCEMYRA 2.88 mg/day or matching placebo). 
Duration of Treatment and Study:  
The study duration for each subject will be up to 85 days. The Screening period is up to 28 days, the 
study drug administration period (including a 4-day study drug taper) is 21 to 27 days (the latter for 
those requiring an extended opioid taper), and a 30-day safety follow-up period. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Criteria for Evaluation: 
Safety: 
The following safety endpoints will be assessed: 
• 
Number and percent of subjects reporting treatment-emergent adverse events (TEAEs) by 
system organ class and preferred term. 
• 
Number and percent of subjects reporting treatment-emergent serious adverse events 
(SAEs) by system organ class and preferred term. 
• 
Number and percent of subjects reporting TEAEs resulting in study drug discontinuation 
by system organ class and preferred term. 
• 
Change in vital signs from Baseline to each scheduled evaluation. 
• 
Change in clinical laboratory values from Baseline to each scheduled evaluation. 
• 
Percentage of subjects with treatment-emergent ALT, AST, or alkaline phosphatase 
>3 × ULN and total bilirubin >2.0 mg/dL at the same evaluation. 
• 
Percentage of subjects identified as suicide risk with C-SSRS. 
Effectiveness: 
The following effectiveness endpoints will assess withdrawal symptoms and pain: 
• 
Percentage of subjects who successfully complete each scheduled dose reduction and the 
opioid taper to complete opioid discontinuation, with or without a pause.  
• 
Change in COWS from Baseline to peak value and to each scheduled evaluation. 
• 
Change in SOWS-H from Baseline to peak value and to each scheduled evaluation. 
• 
Change in SOWS-Gossop from Baseline to peak value and to each scheduled evaluation. 
• 
MCGI-R by each scheduled evaluation. 
• 
MCGI-S by each scheduled evaluation. 
• 
Time to study drug discontinuation. 
• 
Change in daily opioid dose, expressed as MED, and as a percentage of the baseline 
MED. 
• 
Number of non-opioid concomitant medications for withdrawal symptoms used by study 
day. 
• 
Change in average and worst daily pain from Baseline to peak value as measured by the 
NRS. 
• 
Change in EQ-5D-5L from Baseline to each scheduled evaluation. 
• 
Change in SF-36 from Baseline to each scheduled evaluation. 
• 
Change in ISI from Baseline to each scheduled evaluation. 
• 
Change in HADS from Baseline to each scheduled evaluation. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Statistical Methods: 
The treatment group difference in proportions will be summarized descriptively with a 95% 
confidence interval. The 95% confidence interval will be calculated based on the normal 
approximation for the binomial distribution, using the Wald continuity correction. In addition, the 
treatment group difference will be tested with Cochran-Mantel-Haenszel (CMH) test stratified by 
total opioid dose (<90 MED, ≥90 MED. 
The treatment group difference for mean change will be summarized descriptively with 95% 
confidence intervals. The 95% confidence intervals for the treatment group differences will be 
calculated within the framework of analysis of covariance (ANCOVA). The ANCOVA will have 
treatment and total opioid dose (<90 MED, ≥90 MED) as fixed factors and baseline as covariate. In 
addition, the treatment group difference will be tested within the ANCOVA framework. 
Safety data will be summarized with descriptive statistics. Adverse events (AEs) will be categorized 
by system organ class and preferred term with the Medical Dictionary for Regulatory Activities.  
An interim analysis will be conducted after approximately 30 subjects have completed or 
discontinued the study. Based on the interim analysis, the study may be stopped for futility but will 
not be stopped for a positive demonstration of effectiveness. Therefore, no adjustment of Type I error 
is necessary. 
 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
20 
 
 
3.2. 
Schema 
Figure 1: 
Opioid Taper  
 
a Subjects experiencing intolerable opioid withdrawal symptoms may pause the opioid taper, as described in 
Section 9.3. An opioid taper pause includes either a return to the last stable opioid dose for the remainder of the 
current opioid dose reduction period (eg, if a subject experiences intolerable withdrawal at the second reduction 
stage [25% of baseline MED], they can return to the first reduction dose [50% of baseline MED]), or remaining on 
the current opioid dose instead of reducing at the next scheduled reduction, resulting in an overall extended opioid 
taper period and study duration. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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3.3. 
Schedule of Assessments 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Table 2: 
Schedule of Assessments Performed at the Clinic and Phone Calls: Standard Study Schedule 
 
Screeninga 
Study Drug Administrationb 
Safety Follow-up 
Method 
Screening 
RC 
Visit 
1 
PC 1 
Visit 
2 
RC 
 
PC 2 
Visit 
3 
RC 
 
PC 3 
Visit 
4 
RC 
PC 4 Visit 5 PC 5 
EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day  
2 
Day  
3 
Day  
5 
Day  
6 
Day  
7 
Day 
8 
Day  
12 
Day  
13 
Day  
14 
Day  
15 
Day 
17 
Days  
18-21 
Day  
22 
Days  
23-27 Day 28 
Days 
29-50 
Follow
-upc 
Visit window 
 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Informed consent and 
HIPAA authorization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
update 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record Pain 
Management Plan 
X 
Updates should be captured throughout the study 
 
Characterize Baseline 
pain condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Characterize opioid 
use and opioid 
withdrawal historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete PE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief PE  
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine test for opioids 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Urine drug screen for 
illicit substancesf 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
23 
 
 
Screeninga 
Study Drug Administrationb 
Safety Follow-up 
Method 
Screening 
RC 
Visit 
1 
PC 1 
Visit 
2 
RC 
 
PC 2 
Visit 
3 
RC 
 
PC 3 
Visit 
4 
RC 
PC 4 Visit 5 PC 5 
EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day  
2 
Day  
3 
Day  
5 
Day  
6 
Day  
7 
Day 
8 
Day  
12 
Day  
13 
Day  
14 
Day  
15 
Day 
17 
Days  
18-21 
Day  
22 
Days  
23-27 Day 28 
Days 
29-50 
Follow
-upc 
Visit window 
 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Urine test for alcoholg 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Clinical chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
Electrocardiogram 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
COWS 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
SOWS-H and 
SOWS-Gossop 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
MCGI-S 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
MCGI-R 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
NRS chronic pain 
scales 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
NRS all over body 
pain scales 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
EQ-5D-5L 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
SF-36 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ISI 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
HADS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
C-SSRSi 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Dispense diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
24 
 
 
Screeninga 
Study Drug Administrationb 
Safety Follow-up 
Method 
Screening 
RC 
Visit 
1 
PC 1 
Visit 
2 
RC 
 
PC 2 
Visit 
3 
RC 
 
PC 3 
Visit 
4 
RC 
PC 4 Visit 5 PC 5 
EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day  
2 
Day  
3 
Day  
5 
Day  
6 
Day  
7 
Day 
8 
Day  
12 
Day  
13 
Day  
14 
Day  
15 
Day 
17 
Days  
18-21 
Day  
22 
Days  
23-27 Day 28 
Days 
29-50 
Follow
-upc 
Visit window 
 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Diary review and 
check compliance 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Phone callj 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Xk 
 
Xl 
 
Xm 
X 
Reminder contactn 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Opioid dose 
reductiono 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Return study drug 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Dispense/re-dispense 
study drug 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Study drug dosingp 
 
 
Continuously as directed in protocol 
 
 
 
 
 
Subject satisfaction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Subject interviewq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Opioid compliance 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Subject training – 
Reporting of pain and 
opioid withdrawal 
symptoms 
X 
Training should be repeated or reinforced if necessary 
 
 
 
Subject training – 
Vital signsr 
 
 
X 
Training should be repeated if subject has issues using the monitor or demonstrates lack of protocol 
compliance 
 
 
 
Subject training – At 
home diary 
completions 
X 
Training should be repeated if subject demonstrates lack of protocol compliance 
 
 
 
AEs 
 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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Screeninga 
Study Drug Administrationb 
Safety Follow-up 
Method 
Screening 
RC 
Visit 
1 
PC 1 
Visit 
2 
RC 
 
PC 2 
Visit 
3 
RC 
 
PC 3 
Visit 
4 
RC 
PC 4 Visit 5 PC 5 
EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day  
2 
Day  
3 
Day  
5 
Day  
6 
Day  
7 
Day 
8 
Day  
12 
Day  
13 
Day  
14 
Day  
15 
Day 
17 
Days  
18-21 
Day  
22 
Days  
23-27 Day 28 
Days 
29-50 
Follow
-upc 
Visit window 
 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Prior and 
concomitant 
treatments  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; EOS = end of study; EQ-5D-5L = EuroQol 
5-Dimension 5-Level; HADS = Hospital Anxiety and Depression Scale; HIPAA = Heath Insurance Portability and Accountability Act; ISI = Insomnia Severity 
Index; MCGI-R = Modified Clinical Global Impression – Rater Version; MCGI-S = Modified Clinical Global Impression – Subject Version; MED = morphine 
equivalent dose; MINI = Mini-International Neuropsychiatric Interview; PC = phone call; PE = physical examination; RC = reminder contact; SF-36 = Short 
Form Health Survey– 36 items; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; SOWS-H = Subjective Opiate Withdrawal Scale of Handelsman 
a The Screening Visit may be conducted over the course of multiple visits, as needed. 
b Subjects who experience intolerable withdrawal symptoms may temporarily suspend the opioid taper once (Section 9.3). See study drug taper schedule in 
Section 9.2.3. 
c Phone call 30 days after the last dose of study drug. See Table 4 for other assessments to be captured during the phone call, in addition to follow-up on any 
outstanding AEs or concomitant treatment usage. 
d The subject’s baseline opioid use and changes to doses for planned taper reductions should be submitted to and approved by the Medical Monitor prior to 
Day -1. 
e All female subjects, regardless of childbearing potential. 
f Confirmatory quantitative testing for illicit substances identified in qualitative testing results may be performed. 
g Subjects should refrain from alcohol consumption during the study. Repeated alcohol use (eg, 2 positive tests for alcohol after Screening) during the study 
requires subject discontinuation. 
h On Day 1, orthostatic vital signs should be assessed pre-dose and 1-hour post-dose of study drug. A post-dose assessment is not required after Day 1 at clinic 
visits. During phone calls, at-home vital signs (systolic and diastolic blood pressure and pulse) should be recorded after the subject rest for at least 5 minutes. 
i Baseline version at Screening and ‘Since Last Visit’ version at subsequent visits. 
j Phone calls will include review of an at-home vital signs assessment by the subject, an assessment of how the subject is feeling, and review of any changes to 
study drug dosing. 
k Phone call will take place on Day 19, to check on the subject’s well-being and to assess how the subject is feeling. 
l Phone call will take place on Day 25, to check on the subject’s well-being and to assess how the subject is feeling. 
m Phone calls will take place on Days 32, 39, and 46, to check on the subject’s well-being and to assess how the subject is feeling. 
n Reminders contacts may be done via phone, text, or other electronic message. Remind the subjects about opioid dose reductions or, at Day 17, study drug dose 
reductions. 
o Opioid dose will be decreased 50% from baseline MED beginning with the last dose of the day on Day -1, an additional 25% of baseline MED beginning on 
Day 6, and a final 25% (to dose of zero) beginning on Day 13. Opioid dose reduction may not occur on a Friday or Saturday unless the clinic can accommodate 


Protocol 
 
USWM-LX1-2010 Amendment 1 
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subjects on Saturday and Sunday. Subjects who experience intolerable withdrawal symptoms despite increasing their dose of study drug to the maximum 
tolerated dose will be allowed to pause the opioid taper once. See Table 3 for the opioid taper schedule for subjects who must pause the taper. 
p Detailed study drug dosing information can be found in Section 9.2.3. Study drug taper begins on Day 18. 
q Subject interview will be conducted via a centralized interviewer through a phone call. The interview should take place no more than 5 days after the EOS 
Visit. 
r Training includes when to call the site due to symptoms of hypertension or hypotension, or if the subject records a vital signs measurement that meets the 
criteria to contact the site. 
s Training includes recording all pharmacologic and non-pharmacologic concomitant treatments (including opioid medications), study drug dose administration, 
scale assessments for both pain (Average Daily and Worst Daily NRS) and opioid withdrawal scales (SOWS-Gossop, SOWS-Handelsman, and MCGI-
Subject), and recording of at-home vital signs (during study drug taper and through EOS only). 


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27 
 
Table 3: 
Schedule of Assessments Performed at the Clinic and Phone Calls: Study Schedule with Opioid Taper Pause 
 
Screeninga 
Study Drug Administrationb 
 
Safety Follow-up 
Method 
Screenin
g 
RC 
Visit 
1 
PC 1 Visit 2 RC 
 
PC 2 Visit 3 RC 
 
PC 3 
Visit 
4 
RC 
 
PC 
3P 
Visit 
4P 
RC PC 4 Visit 5 PC 5 EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day 
2 
Day  
3 
Day  
5 
Day 
6 
Day 
7 
Day 
8 
Day  
12 
Day  
13 
Day 
14 
Day  
15 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
23 
Days 
24-
27 
Day  
28 
Days 
29-
33 Day 34 
Days 
35-56 
Follow
-upc 
Visit window 
 
 
 
 
±1 day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Informed consent 
and HIPAA 
authorization  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusio
n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
updat
e 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record Pain 
Management Plan 
X 
Updates should be captured throughout the study 
 
Characterize 
Baseline pain 
condition 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Characterize 
opioid use and 
opioid withdrawal 
historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete PE  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief PE  
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
28 
 
 
Screeninga 
Study Drug Administrationb 
 
Safety Follow-up 
Method 
Screenin
g 
RC 
Visit 
1 
PC 1 Visit 2 RC 
 
PC 2 Visit 3 RC 
 
PC 3 
Visit 
4 
RC 
 
PC 
3P 
Visit 
4P 
RC PC 4 Visit 5 PC 5 EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day 
2 
Day  
3 
Day  
5 
Day 
6 
Day 
7 
Day 
8 
Day  
12 
Day  
13 
Day 
14 
Day  
15 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
23 
Days 
24-
27 
Day  
28 
Days 
29-
33 Day 34 
Days 
35-56 
Follow
-upc 
Visit window 
 
 
 
 
±1 day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Urine pregnancy 
teste 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine test for 
opioids 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Urine drug screen 
for illicit 
substancesf 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Urine test for 
alcoholg 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Clinical chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
 
X 
 
 
Electrocardiogram 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
COWS 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
SOWS-H and 
SOWS-Gossop 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
MCGI-S 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
MCGI-R 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
NRS chronic pain 
scales 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
NRS all over body 
pain scales 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
EQ-5D-5L 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
29 
 
 
Screeninga 
Study Drug Administrationb 
 
Safety Follow-up 
Method 
Screenin
g 
RC 
Visit 
1 
PC 1 Visit 2 RC 
 
PC 2 Visit 3 RC 
 
PC 3 
Visit 
4 
RC 
 
PC 
3P 
Visit 
4P 
RC PC 4 Visit 5 PC 5 EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day 
2 
Day  
3 
Day  
5 
Day 
6 
Day 
7 
Day 
8 
Day  
12 
Day  
13 
Day 
14 
Day  
15 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
23 
Days 
24-
27 
Day  
28 
Days 
29-
33 Day 34 
Days 
35-56 
Follow
-upc 
Visit window 
 
 
 
 
±1 day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
SF-36 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ISI 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
HADS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
C-SSRSi 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Dispense diary 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary review and 
check compliance 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Phone callj 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Xk 
 
Xl 
 
Xm 
X 
Reminder contactn 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Opioid dose 
reductiono 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Return study drug 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
Dispense/re-
dispense study 
drug 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
Study drug 
dosingp 
 
 
Continuously as directed in protocol 
 
 
 
 
 
Subject 
satisfaction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Subject interviewq 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Opioid 
compliance 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
30 
 
 
Screeninga 
Study Drug Administrationb 
 
Safety Follow-up 
Method 
Screenin
g 
RC 
Visit 
1 
PC 1 Visit 2 RC 
 
PC 2 Visit 3 RC 
 
PC 3 
Visit 
4 
RC 
 
PC 
3P 
Visit 
4P 
RC PC 4 Visit 5 PC 5 EOS 
PCs 
6,7,8 
30-day 
PC 9 
Timing 
Days 
-28 to -2 
Day 
-1 
Day  
1 
Day 
2 
Day  
3 
Day  
5 
Day 
6 
Day 
7 
Day 
8 
Day  
12 
Day  
13 
Day 
14 
Day  
15 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
23 
Days 
24-
27 
Day  
28 
Days 
29-
33 Day 34 
Days 
35-56 
Follow
-upc 
Visit window 
 
 
 
 
±1 day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
 
±1 
day 
 
 
±1 day 
 
±1 day 
 
 
Subject training – 
Reporting of pain 
and opioid 
withdrawal 
symptoms 
X 
Training should be repeated or reinforced if necessary 
 
 
 
Subject training – 
Vital signsr 
X 
 
X 
Training should be repeated if subject has issues using the monitor or demonstrates lack of protocol compliance 
 
 
 
Subject training – 
At home diary 
completions 
X 
Training should be repeated if subject demonstrates lack of protocol compliance 
 
 
 
AEs 
X 
 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
Prior and 
concomitant 
treatments  
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; C-SSRS = Columbia-Suicide Severity Rating Scale; EOS = end of study; EQ-5D-5L = EuroQol 
5-Dimension 5-Level; HADS = Hospital Anxiety and Depression Scale; HIPAA = Heath Insurance Portability and Accountability Act; ISI = Insomnia Severity 
Index; MCGI-R = Modified Clinical Global Impression – Rater Version; MCGI-S = Modified Clinical Global Impression – Subject Version; MED = morphine 
equivalent dose; MINI = Mini-International Neuropsychiatric Interview; PC = phone call; PE = physical examination; RC = reminder contact; SF-36 = Short 
Form Health Survey– 36 items; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; SOWS-H = Subjective Opiate Withdrawal Scale of Handelsman 
a The Screening Visit may be conducted over the course of multiple visits, as needed. 
b Subjects who experience intolerable withdrawal symptoms may temporarily suspend the opioid taper once (Section 9.3). See study drug taper schedule in 
Section 9.2.3. 
c Phone call 30 days after the last dose of study drug. See Table 5 for other assessments to be captured during the phone call, in addition to follow-up on any 
outstanding AEs or concomitant treatment usage. 
d The subject’s baseline opioid use and changes to doses for planned taper reductions should be submitted to and approved by the Medical Monitor prior to 
Day -1. 
e All female subjects, regardless of childbearing potential. 
f Confirmatory quantitative testing for illicit substances identified in qualitative testing results may be performed. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
31 
 
g Subjects should refrain from alcohol consumption during the study. Repeated alcohol use (eg, 2 positive tests for alcohol after Screening) during the study 
requires subject discontinuation. 
h On Day 1, orthostatic vital signs should be assessed pre-dose and 1-hour post-dose of study drug. A post-dose assessment is not required after Day 1 at clinic 
visits. During phone calls, at-home vital signs (systolic and diastolic blood pressure and pulse) should be recorded after the subject rest for at least 5 minutes. 
i Baseline version at Screening and ‘Since Last Visit’ version at subsequent visits. 
j Phone calls will include review of an at-home vital signs assessment by the subject, an assessment of how the subject is feeling, and review of any changes to 
study drug dosing. 
k Phone call will take place on Day 25, to check on the subject’s well-being and to assess how the subject is feeling. 
l Phone call will take place on Day 31, to check on the subject’s well-being and to assess how the subject is feeling. 
m Phone calls will take place on Days 38, 45, and 52, to check on the subject’s well-being and to assess how the subject is feeling. 
n Reminders contacts may be done via phone, text, or other electronic message. Remind the subjects about opioid dose reductions or, at Day 24, study drug dose 
reductions. 
o Opioid dose will be decreased 50% from baseline MED beginning with the last dose of the day on Day -1. The opioid dose will be decreased or maintained 
beginning on Day 6. The opioid dose will be decreased an additional 25% of baseline MED or maintained beginning on Day 13. A final 25% (to dose of zero) 
reduction will be made beginning on Day 19. Subjects who experience intolerable withdrawal symptoms despite increasing their dose of study drug to the 
maximum tolerated dose will be allowed to pause the opioid taper once. Pausing the opioid taper includes either a return to the last stable opioid dose for the 
remainder of the current opioid dose reduction period (eg, if a subject experiences intolerable withdrawal at the second reduction stage [25% of baseline MED], 
they can return to the first reduction dose [50% of baseline MED]), or remaining on the current opioid dose instead of reducing at the next scheduled reduction, 
resulting in an overall extended opioid taper period and study duration. In this scenario, a subject will taper to a dose of zero beginning on Day 19. Opioid dose 
reduction may not occur on a Friday or Saturday unless the clinic can accommodate subjects on Saturday and Sunday. 
p Detailed study drug dosing information can be found in Section 9.2.3. Study drug taper begins on Day 24. 
q Subject interview will be conducted via a centralized interviewer through a phone call. The interview should take place no more than 5 days after the EOS 
Visit. 
r Training includes when to call the site due to symptoms of hypertension or hypotension, or if the subject records a vital signs measurement that meets the 
criteria to contact the site. 
s Training includes recording all pharmacologic and non-pharmacologic concomitant treatments (including opioid medications), study drug dose administration, 
scale assessments for both pain (Average Daily and Worst Daily NRS) and opioid withdrawal scales (SOWS-Gossop, SOWS-Handelsman, and 
MCGI-Subject), and recording of at-home vital signs (during study drug taper and through EOS only). 


Protocol 
 
USWM-LX1-2010 Amendment 1 
32 
 
Table 4: 
Schedule of Assessments Performed at Home: Standard Study Schedule 
 
Screening 
Study Drug Administrationa 
Safety Follow-up 
Timing 
Days 
-28 to -2 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Days 
22-27 
Follow-
upb 
Site contactc 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
SOWS-H and 
SOWS-Gossopd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MCGI-Sd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS chronic pain 
scalesd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS all over 
body pain scalesd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Record study drug 
and concomitant 
treatment used 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs – 
Phone reportf 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs – 
Subject diaryg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
AEs 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
AE = adverse event; EOS = end of study; EQ-5D-5L = EuroQol 5-Dimension 5-Level; MCGI-S = Modified Clinical Global Impression – Subject Version; 
NRS = Numeric Rating Scale; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; SOWS-H = Subjective Opiate Withdrawal Scale of Handelsman 
a Subjects who experience intolerable withdrawal symptoms may temporarily suspend the opioid taper once (Section 9.3). See study drug taper schedule 
(Section 9.2.3). See Table 5 for the schedule of assessments to be performed at home for subjects who must pause the taper. 
b Phone call 30 days after the last dose of study drug. Subjects will be asked to report their current opioid dose/regimen and complete several scales (EQ-5D-5L 
and NRS pain scales) over the phone. 
c Reminder contacts will take place on Days -1, 5, 12, and 17. Phone calls from the clinic staff will take place on Days 2, 7, 14, 25, 32, 39, 46, and 30 days 
following the last dose of study drug (follow-up phone call). A subject phone interview, conducted by a centralized interviewer, will take place between 
Days 28 and 33. 
d Completed at home before bedtime. 
e Subjects will continue to complete the NRS chronic pain scales every day between the EOS Visit and the phone call 30 days following the last dose of study 
drug (follow-up phone call). 
f During the phone call to the subject, the site should ask the subject to collect and report their vital signs. The subject will not record this reading in their diary. 
g Readings will be taken once in the morning and once in the evening and reported in the subject’s diary.


Protocol 
 
USWM-LX1-2010 Amendment 1 
33 
 
Table 5: 
Schedule of Assessments Performed at Home: Study Schedule with Opioid Taper Pause 
 
Screening 
Study Drug Administrationa 
Safety 
Follow-up 
Timing 
Days 
-28 to -2 Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Day 
14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Day 
27 
Days 
28-
33 
Follow-
upb 
Site contactc 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
SOWS-H and 
SOWS-Gossopd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MCGI-Sd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NRS chronic pain 
scalesd,e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
NRS all over body 
pain scalesd 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Record study drug 
and concomitant 
treatment used 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs – Phone 
reportf 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs – 
Subject diaryg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
AEs 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
AE = adverse event; EOS = end of study; EQ-5D-5L = EuroQol 5-Dimension 5-Level; MCGI-S = Modified Clinical Global Impression – Subject Version; 
NRS = Numeric Rating Scale; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; SOWS-H = Subjective Opiate Withdrawal Scale of Handelsman 
a Subjects who experience intolerable withdrawal symptoms may temporarily suspend the opioid taper once (Section 9.3). See study drug taper schedule 
(Section 9.2.3). 
b Phone call 30 days after the last dose of study drug. Subjects will be asked to report their current opioid dose/regimen and complete several scales (EQ-5D-5L 
and NRS pain scales) over the phone. 
c Reminder contacts will take place on Days -1, 5, 12, 18, and 23. Phone calls from the clinic staff will take place on Days 2, 7, 14, 20, 25, 31, 38, 45, 52, and 
30 days following the last dose of study drug (follow-up phone call). A subject phone interview, conducted by a centralized interviewer, will take place 
between Days 34 and 39. 
d Completed at home before bedtime. 
e Subjects will continue to complete the NRS chronic pain scales every day between the EOS Visit and the phone call 30 days following the last dose of study 
drug (follow-up phone call). 
f During the phone call to the subject, the site should ask the subject to collect and report their vital signs. The subject will not record this reading in their diary. 
g Readings will be taken once in the morning and once in the evening and reported in the subject’s diary.


Protocol 
 
USWM-LX1-2010 Amendment 1 
34 
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 6: 
List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMDG 
Agency Medical Director’s Group 
ANOVA 
Analysis of variance 
AST 
aspartate aminotransferase 
CDC 
Centers for Disease Control 
CFR 
Code of Federal Regulation 
CMH 
Cochran-Mantel-Haenszel 
CNS 
Central nervous system 
COWS 
Clinical Opiate Withdrawal Scale 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DILI 
Drug-induced liver injury 
DMC 
Data Monitoring Committee 
eCRF 
Electronic case report form 
EERW 
Enriched enrollment randomized withdrawal 
EOS 
End of study 
EQ-5D-5L 
EuroQol 5-Dimension 5-Level 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISI 
Insomnia Severity Index 
ITT 
Intent-to-treat 
MCGI-R 
Modified Clinical Global Impression – Rater Version 
MCGI-S 
Modified Clinical Global Impression – Subject Version 
MED 
Morphine equivalent dose 
MME 
Morphine mg equivalents 


Protocol 
 
USWM-LX1-2010 Amendment 1 
35 
 
Abbreviation 
Definition 
NRS 
Numeric Rating Scale 
OIC 
Opioid-induced constipation 
OUD 
Opioid use disorder 
QID  
4 times per day 
QTcF 
QT corrected by heart rate by Fridericia's method 
SAE 
Serious adverse event 
SF-36 
Short Form Health Survey– 36 items 
SOWS-Gossop 
Short Opiate Withdrawal Scale of Gossop 
SOWS-H 
Subjective Opiate Withdrawal Scale of Handelsman 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
Abbreviations that appear only in tables or figures are defined with the relevant tables and figures. 
 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
36 
 
5. 
INTRODUCTION 


Protocol 
 
USWM-LX1-2010 Amendment 1 
37 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
38 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
39 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
40 
 


Protocol 
 
USWM-LX1-2010 Amendment 1 
41 
 
6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective is to evaluate the safety and tolerability of LUCEMYRA versus placebo 
when used during an opioid taper in subjects with chronic non-cancer pain. 
6.2. 
Secondary Objectives 
The secondary objectives of this study are to estimate the difference between treatment groups 
in: 
• Measures related to opioid withdrawal and completion of opioid discontinuation 
when tapered 
• Measures of effectiveness in pain relief, quality of life, and treatment satisfaction 
6.4. 
Assessment Tools Used to Achieve Objectives 
The assessment tools used to achieve the study objectives are presented in Table 7. Effectiveness 
and safety endpoints, based on these assessment tools, are defined in Section 7.2. 


Protocol 
 
USWM-LX1-2010 Amendment 1 
42 
 
Table 7: 
Assessment Tools Used to Achieve Objectives 
Objective 
Assessment Tools 
Primary Objective 
 
Evaluate the safety and tolerability of 
LUCEMYRA versus placebo when used 
during an opioid taper in subjects with 
chronic non-cancer pain 
AE reports, clinical laboratory assessments, monitoring 
of DILI, vital signs, and C-SSRS 
Secondary Objectives 
 
Estimate the difference between treatment 
groups in measures related to opioid 
withdrawal and completion of opioid 
discontinuation when tapered 
Taper completion status, reduction in opioid use, urine 
drug screen, COWS, MCGI-R, MCGI-S, 
SOWS-Gossop, SOWS-H 
Estimate the difference between treatment 
groups in measures of effectiveness in 
pain relief, quality of life, and treatment 
satisfaction  
EQ-5D-5L, HADS, ISI, NRS, SF-36, subject 
satisfaction, and use of rescue medication for pain 
AE = adverse event; COWS = Clinical Opiate Withdrawal Scale; C-SSRS = Columbia-Suicide Severity Rating 
Scale; DILI = drug-induced liver injury; EQ-5D-5L = EuroQol 5-Dimension 5-Level; HADS = Hospital Anxiety 
and Depression Scale; ISI = Insomnia Severity Index; MCGI-R = Modified Clinical Global Impression – Rater 
Version; MCGI-S = Modified Clinical Global Impression – Subject Version; NRS = Numeric Rating Scale; 
SF-36 = Short Form Health Survey – 36 Items; SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop; 
SOWS-H = Subjective Opiate Withdrawal Scale of Handelsman 


Protocol 
 
USWM-LX1-2010 Amendment 1 
43 
 
7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a pilot, multicenter, randomized, double-blind, placebo-controlled, outpatient clinical trial 
to assess the safety and tolerability, and to estimate the effectiveness of LUCEMYRA for 
mitigating the symptoms of opioid withdrawal in the setting of an opioid taper in subjects with 
chronic non-cancer pain. 
After a Screening period of up to 28 days, subjects will begin a planned 14-day complete taper of 
their pre-study opioid and will be randomly assigned (1:1) to either LUCEMYRA or matching 
placebo. Study drug will be administered through the opioid taper and for 5 days after the opioid 
taper is completed. Study drug will then be tapered over a 4-day period for a total of 
approximately 21 days exposure to study drug (Figure 1). 
Day 1 dosing with study drug will begin in the clinic as 1 tablet (LUCEMYRA 0.18 mg/tablet or 
matching placebo) 4 times per day (QID) for a total daily dose of LUCEMYRA 0.72 mg or 
matching placebo. Subjects will be instructed to take their study drug in the morning upon 
awakening and then every 5 to 6 hours thereafter. Doses should be taken 5 to 6 hours apart and 
no more than 4 times per day. At the Day 1 Visit (Visit 1), the Investigator should schedule a 
phone call with the subject, to occur prior to the second dose of study drug on Day 2, to review 
the subjects at-home vital signs measurement and how the subject is feeling. The subject will be 
instructed to contact the site if they experience signs or symptoms of hypotension, bradycardia, 
or orthostasis (eg, lightheadedness, slow heart rate, dizziness, feeling faint at rest or when 
standing up) while continuing to dose at home on Day 1. If the subject contacts the site on Day 1 
reporting these symptoms, the Investigator should consider reducing the planned first daily dose 
on Day 2. 
On Day 2 the subject will be instructed to take 2 tablets QID (LUCEMYRA 1.44 mg/day or 
matching placebo), unless Day 1 dosing was not well-tolerated. The subject should contact the 
site if they experience signs or symptoms of hypotension, bradycardia, or orthostasis (eg, 
lightheadedness, slow heart rate, dizziness, feeling faint at rest or when standing up) after the 
first daily dose. The Investigator will contact the subject on Day 2, prior to the second dose of 
the day, to review the subject’s at-home vital signs measurement and how the subject is feeling. 
The Investigator should discuss with the subject any changes to dosing of study drug. Dosing 
instructions may include an increase to 3-tablets per dose due to subject report of intolerable 
opioid withdrawal symptoms, or a reduction back to 1 tablet per dose, due to intolerability of 
study drug. 
On Day 3 and beyond, dosing will be at the discretion of the Investigator, as guided by subject 
tolerability of study drug and opioid withdrawal symptoms. 
The dose of study drug may be increased to manage opioid withdrawal symptoms. If an 
increased dose of study drug is not well-tolerated, the dose can be decreased. A single dose of 
study drug should not exceed 4 tablets (LUCEMYRA 0.72 mg or matching placebo). The total 
daily dose of study drug should not exceed 4 tablets QID (LUCEMYRA 2.88 mg/day or 
matching placebo). 
Subjects will be tapered from their baseline total daily dose of opioid (calculated as MED) over a 
14-day period. The opioid dose will be decreased as close as possible to achieve the following 


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dose reduction targets: 50% from the baseline MED beginning with the last dose of the day on 
Day -1, an additional 25% of the baseline MED beginning on Day 6, and a final 25% of the 
baseline MED (to dose of zero) beginning on Day 13 (Figure 1). Reminders for opioid dose 
reduction may be done via phone, text, or other electronic message. 
The Investigator will instruct the subject on how to reduce their opioid dosing regimen for each 
dose reduction. Opioid dosing to achieve the required dose reductions in accordance with the 
protocol defined taper must be planned during Screening. Any changes in opioid prescription to 
facilitate the protocol taper should be discussed with the subject’s primary pain physician, when 
applicable, and prescribed in advance of randomization. The Investigator should work with a 
preferred pharmacy informed about the subject’s participation in a clinical trial in order to fulfill 
prescribing needs to facilitate the opioid taper. Opioid prescriptions should be written to 
accommodate the planned taper, as specified per protocol in Section 9.3. The subject’s baseline 
opioid regimen and MED calculation as well as the opioid regimen planned to achieve each taper 
step should be submitted to and approved by the Medical Monitor prior to Day -1. 
Non-opioid medications taken during the study should be in compliance with the allowed 
concomitant treatments in Section 9.4. Opioid dose reductions may not occur on a Friday or 
Saturday unless clinic can accommodate subjects on Saturday and Sunday. Qualified study 
personnel at the clinic should call the subject the day after the opioid dose is decreased (except 
on Day 1 since the subject will come to the clinic) to review the subject’s at-home vital signs 
measurement and how the subject is feeling. Upon review by the Investigator or designee, 
changes to dosing of study drug should also be discussed with the subject if applicable. 
Subjects who experience intolerable withdrawal symptoms despite increasing their dose of study 
drug to the maximum tolerated dose (not to exceed 4 tablets QID) will be allowed to pause the 
opioid taper once. Pausing the opioid taper includes either a return to the last stable opioid dose 
for the remainder of the current opioid dose reduction period, or remaining on the current opioid 
dose instead of reducing at the next scheduled reduction, resulting in an overall extended opioid 
taper period and study duration. For example, if a subject experiences intolerable withdrawal at 
the second opioid dose reduction step [25% of baseline MED], they may either 1) return to the 
first reduction dose [50% of baseline MED]) or, 2) when the withdrawal persists until the next 
scheduled reduction step, they may remain for longer at the current opioid dose [25% of baseline 
MED]. In both cases, the taper must be resumed following the single pause in accordance with 
the protocol schedule. Subjects who cannot or are unwilling to continue the opioid taper after one 
pause will be discontinued from the study. 
Decisions on whether to pause the opioid taper will be based on subject request and an 
evaluation (in clinic or over the phone) of the subject’s status by the Investigator. Subjects may 
request to pause the opioid taper due to opioid withdrawal symptoms. If the subject’s last COWS 
score is ≥5 OR if based on i) the Investigator’s discussion with the subject, ii) review of ongoing 
subject-reported withdrawal related AEs, and iii) most recent scores for subject reported 
withdrawal scales, the subject’s desire to pause the taper is related primarily to opioid 
withdrawal discomfort in the Investigator’s opinion, then the taper may be paused. In the event 
that the Investigator assesses the subject’s desire to pause the taper to be primarily related to 
pain, a taper pause will not be permitted; however, if the subject is willing to continue the per 
protocol taper, recommended modifications to their concurrent pain management plan should be 


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discussed and recorded. Subjects unwilling to continue the per protocol taper and not experiencing 
opioid withdrawal to permit a single pause should be discontinued from the study.  
Study drug dosing for an opioid taper pause will remain at the discretion of the Investigator, as 
guided by subject tolerability of study drug and opioid withdrawal symptoms. The dose of study 
drug can be increased or decreased as needed. 
Dosing of study drug will continue for 5 days after the last opioid dose. Study drug will then be 
tapered over an additional 4 days (Section 9.2.3).  
Subjects will be given a diary to take home and will use it to complete daily questionnaires 
regarding withdrawal and other symptoms, average and worst daily pain, record opioid and study 
drug administration and concomitant treatment use (including use of medication for pain or 
opioid withdrawal symptoms). 
Subjects will take their blood pressure and heart rate at home using a vital sign monitor. At home 
readings will be collected during phone calls conducted by study staff after each opioid dose 
reduction and twice daily (morning and evening) during the 4-day study drug taper through the 
EOS Visit. Subjects will record readings in their diary.  
Subjects who experience pain will be allowed to take treatments described in Section 9.4.2. Use 
of treatments for pain and concomitant medications to treat withdrawal symptoms will be 
recorded daily by subjects using their diary. 
Subjects will return to the clinic on Day 3, Day 8, and then on a weekly basis following 
randomization during the study drug administration for assessments. With the exception of Day 1 
(Visit 1), clinic visits can occur ±1 day from the study-specified timepoint. Subjects will return 
to the clinic approximately 7 days after their last dose of study drug. At 30 days following the 
last dose of study drug, subjects will receive a telephone call for a safety follow-up and 
assessment of the subject’s current opioid usage, after which their participation in the study will 
be complete. 
Subjects who prematurely discontinue the study will be instructed to taper study drug as 
described in Section 9.2.3 and to complete the at-home assessments for the study drug taper 
period (Table 4 or Table 5). Once discontinued, subjects may not re-enter the study. 
7.2. 
Study Endpoints 
7.2.1. 
Safety Endpoints 
The following safety endpoints will be assessed: 
• Number and percent of subjects reporting treatment-emergent adverse events 
(TEAEs) by system organ class and preferred term. 
• Number and percent of subjects reporting treatment-emergent serious adverse events 
(SAEs) by system organ class and preferred term. 
• Number and percent of subjects reporting TEAEs resulting in study drug 
discontinuation by system organ class and preferred term. 
• Change in vital signs from Baseline to each scheduled evaluation. 


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• Change in clinical laboratory values from Baseline to each scheduled evaluation. 
• Percentage of subjects with treatment-emergent alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), or alkaline phosphatase >3 × the upper limit of 
normal (ULN) and total bilirubin >2.0 mg/dL at the same evaluation. 
• Percentage of subjects identified as suicide risk with Columbia-Suicide Severity 
Rating Scale (C-SSRS). 
7.2.2. 
Effectiveness Endpoints 
The following effectiveness endpoints will assess withdrawal symptoms and pain: 
• Percentage of subjects who successfully complete each scheduled dose reduction and 
the opioid taper to complete opioid discontinuation, with or without a pause. 
• Change in COWS from Baseline to peak value and to each scheduled evaluation. 
• Change in SOWS-H from Baseline to peak value and to each scheduled evaluation. 
• Change in SOWS-Gossop from Baseline to peak value and to each scheduled 
evaluation. 
• Modified Clinical Global Impression – Rater Version (MCGI-R) by each scheduled 
evaluation. 
• Modified Clinical Global Impression – Subject Version (MCGI-S) by each scheduled 
evaluation. 
• Time to study drug discontinuation. 
• Change in daily opioid dose, expressed as MED, and as a percentage of the baseline 
MED. 
• Number of non-opioid concomitant medications for withdrawal symptoms used by 
study day. 
• Change in average and worst daily pain from Baseline to peak value as measured by 
the Numeric Rating Scale (NRS). 
• Change in EuroQol 5-Dimension 5-Level (EQ-5D-5L) scale from Baseline to each 
scheduled evaluation. 
• Change in Short Form Health Survey – 36 Items (SF-36) scale from Baseline to each 
scheduled evaluation. 
• Change in Insomnia Severity Index (ISI) from Baseline to each scheduled evaluation. 
• Change in Hospital Anxiety and Depression Scale (HADS) from Baseline to each 
scheduled evaluation. 


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7.3. 
Number of Subjects 
A total of 60 subjects will be randomized in a 1:1 ratio to LUCEMYRA (30 subjects) and 
placebo (30 subjects). 
7.4. 
Duration of Subject Participation  
The study duration for each subject will be up to 85 days. The Screening period is up to 28 days, 
the study drug administration period (including a 4-day study drug taper) is 21 to 27 days (the 
latter for those requiring an extended opioid taper), and a 30-day safety follow-up period. 
7.5. 
Treatment Assignment 
See Section 9.1.1. 
7.6. 
Adjustment Criteria for Opioid Taper 
See Section 9.3. 
7.7. 
Sponsor Criteria for Study Termination  
The Sponsor has the right to terminate the study or suspend enrollment at an individual site at 
any time. The Investigator will be notified by telephone and in writing if the Sponsor decides to 
suspend or terminate the study for any reason. The written notice will provide the Investigator 
with the reason that the site and/or study was suspended or terminated along with instructions on 
how the site should proceed. 
Reasons for terminating the study may include, but are not limited to, the following: 
• Discovery (from this or other studies) of an unexpected, serious, or unacceptable 
health hazard to subjects 
• A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product 
• Evidence from the data that there are sufficient technical problems with the study to 
believe with a high degree of certainty that subjects are being exposed without a 
realistic expectation of evaluable data 
• Subject enrollment is unsatisfactory  
• Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data that threaten the scientific integrity 
of the study 


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Reasons for suspending enrollment at a site may include, but are not limited to, the following: 
• Failure of the Investigator to comply with pertinent regulatory regulations 
• Submission of knowingly false information from the research facility to the Sponsor 
• Subject enrollment is unsatisfactory 
• Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data that threaten the scientific integrity 
of the study 


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8. 
SELECTION AND DISCONTINUATION OF SUBJECTS 
Before performing any study-specific procedure, the appropriate written informed consent and 
Health Insurance Portability and Accountability Act authorization must be obtained. A screening 
window of up to 28 days is provided to ensure the Investigator has adequate time to evaluate the 
subject’s medical history, Screening laboratory tests, and other eligibility criteria. The Screening 
Visit may be conducted over the course of multiple visits, as needed. Investigators will be 
expected to maintain a Screening log of all potential study candidates that includes limited 
information about the potential candidate (eg, date of Screening).  
8.1. 
Subject Inclusion Criteria 
1. Subject can provide written informed consent. 
2. Subject is willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
3. Chronic non-cancer pain diagnosis such as low back pain, chronic neck pain, 
osteoarthritis, and prolonged post-surgical pain with daily pain for a minimum of 
6 months. 
4. Men and women at least 18 years of age at the time of signing informed consent. 
5. Self-reported use of prescribed oral opioid medication(s), taken as tablets, pills, or capsules, 
of at least 50 morphine mg equivalent (MME) but no higher than 240 mg MME daily or 
near daily (≥5 days per week) for at least 12 weeks and seeking to discontinue their 
opioid medication. MMEs must be calculated using conversion factors recommended by 
the Center for Disease Control and Prevention to confirm the MED for the day is between 
50-240 MME, including both breakthrough and around-the-clock pain medications, at 
Screening. The Medical Monitor must review and approve all baseline opioid use 
consumption and planned taper dosing regimens prior to Day -1. 
6. Willing to be treated with non-opioid treatments for pain (in addition to opioid being 
tapered) for the duration of the study. 
7. Subject agrees to follow the opioid taper plan, both in terms of the planned changes in the 
doses of opioid medications and the schedule for when opioid dose reductions will be 
made, as outlined by the Investigator and approved by the study Medical Monitor.   
8. Subject agrees to partner with his or her pain physician on a subject-centered pain 
management program during the study. 
9. If the subject is not normally a patient at the clinic, the subject’s normal pain physician 
must sign an attestation that the physician agrees to resume the subject’s pain 
management care following the study. 
10. In generally good health, in the opinion of the Investigator, other than the underlying 
chronic pain syndrome at Screening based upon the results of a medical history, physical 
examination, 12-lead electrocardiogram, and laboratory profile. 
11. Subject agrees to abstain from use of alcohol during the study. 
12. Women of childbearing potential must have a negative pregnancy test at Screening. 


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13. Non-pregnant, non-lactating women who are postmenopausal, naturally or surgically 
sterile, or who agree to use acceptable contraceptive methods throughout the course of 
the study. Postmenopausal is defined as at least 12 months of amenorrhea, or at least 
6 weeks following surgical menopause, defined as bilateral oophorectomy, tubal ligation, 
or hysterectomy. If of childbearing potential, subject must have been using birth control 
for at least 30 days and must agree to use one of the following methods of birth control: 
• Oral contraceptives 
• Patch 
• Barrier method (diaphragm, sponge, or condom) with spermicidal preparations 
• Intrauterine contraceptive system 
• Levonorgestrel implant 
• Medroxyprogesterone acetate contraceptive injection 
• Complete abstinence from sexual intercourse 
• Hormonal vaginal contraceptive ring; surgical sterilization, or partner sterile 
14. If male, must agree to use one of the birth control methods listed in inclusion criterion 13 
throughout the entire study period and for 90 days after the last dose of study drug. Must 
not donate sperm for 90 days after the last dose of study drug. 
15. Able to speak, write, and understand English, understand the consent form, and be able to 
effectively communicate with the study staff. 
8.2. 
Subject Exclusion Criteria 
1. Has a primary diagnosis of complex regional pain syndrome, central neuropathic pain, 
somatoform pain syndromes, acute nerve root compression, any acute or progressive 
infectious, inflammatory, or neurological process. 
2. Liver disease that requires medication or medical treatment, and/or AST or ALT levels 
greater than 3 times the ULN. 
3. Gastrointestinal or renal disease, which would significantly impair absorption, 
metabolism or excretion of study drug, or would require medication or medical treatment. 
4. Has a diagnosis of epilepsy or history of seizures. 
5. Has clinically significant abnormal laboratory value(s). 
6. Self-reported or evidence of OUD or other substance use disorder within last 12 months 
prior to Screening using the Sponsor-provided Mini-International Neuropsychiatric 
Interview. 
7. Urine toxicology screen positive for any illicit or non-prescribed opioid drugs prior to 
randomization. 
8. Taking prescription methadone, buprenorphine, fentanyl rapid acting products, tapentadol, 
tramadol, butorphanol, meperidine, or levorphanol for any reason. 


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9. Known or suspected pregnancy, planned pregnancy, or lactation. 
10. Any of the following cardiovascular abnormalities at Screening and before 
randomization: 
a. Resting heart rate ≥105 bpm or <55 bpm or symptomatic bradycardia; 
b. Resting systolic blood pressure ≥160 mmHg or <95 mmHg or symptomatic 
hypotension; 
c. Resting diastolic blood pressure ≥90 mmHg or <65 mmHg; 
d. Clinically significant abnormal electrocardiogram (eg, second- or third-degree heart 
block, uncontrolled arrhythmia; QT corrected by heart rate by Fridericia's method 
(QTcF) of ≥450 msec or a history of QT interval prolongation; 
e. New York Heart Association class III or IV; or 
f. History of myocardial infarction within 6 months of Screening. 
Medications taken for stable hypertension are permitted when dose/regimen has been 
consistent for a minimum of 3 months prior to screening. 
11. Any severe or unstable psychiatric disorder including post-traumatic stress disorder, 
schizophrenia, bipolar disorder, major depression, substance abuse, or suicidality as 
determined by the Investigator. 
12. Subject answers “yes” to “suicidal ideation” in prior 24 months to any items 1 through 5 
on the C-SSRS, or subject answers “yes” to any lifetime “suicidal behavior” item on the 
C-SSRS. 
13. Requires any of the following medications currently or within the past 30 days: 
a. Alpha-2 adrenergic agonists 
b. Antiarrhythmics 
c. Barbiturates 
d. Paraldehyde 
e. Stiripentol 
f. Psychoactive herbal preparations (including St. John’s Wort, Kratom, cannabis, and 
products containing cannabinoids) 
g. Aspirin (baby aspirin permitted if taking prior to study for prophylactic purposes) 
14. Medications given for stable neuro-psychiatric diagnoses must be at a consistent 
dose/regimen for at least 30 days prior to randomization. CNS depressants in 
combination with lofexidine may increase the risk of hypotension and bradycardia. 
Acceptable regular, stable-dosing medications within this category include:   
a. Strong cytochrome P450-2D6 inhibitors, muscle relaxants, benzodiazepines, 
hypnotics, soporifics, tricyclic antidepressants, selective serotonin reuptake inhibitors, 
permitted anticonvulsants (including but not limited to gabapentin and pregabalin) 
must be taken at doses within the ranges recommended per product labeling. 
b. Subject must meet all other eligibility criteria while at the established stable 
dose/regimen and the medication must be continued at the same dose/regimen for the 
duration of the study drug administration period.  


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c. If taken on an as needed basis, subjects should discontinue medications in these 
categories 2 weeks prior to randomization and avoid use for the duration of the study 
drug administration period. 
d. No more than 1 drug in each class should be part of the stable regimen (eg, subjects 
taking 2 permitted muscle relaxants, 2 anticonvulsants, 2 hypnotics, or 2 soporifics 
should be excluded until they are taking no more than 1 drug in each class). 
15. Treatment with an investigational drug, device, or biological agent within 30 days before 
Screening or while participating in this study. 
16. Any anticipated or scheduled surgery during the study period. 
17. Major surgery within 30 days before Screening. 
18. Metastatic cancer diagnosed within the previous year or diagnosis of any malignancy or 
neoplasm within 3 months prior to Screening, exclusive of basal cell carcinoma.  
19. Has self-reported acquired immunodeficiency syndrome or self-reported human 
immunodeficiency virus positive status.  
20. History of lack of tolerance or lack of response to LUCEMYRA which in the 
Investigator’s opinion, makes the subject a poor candidate for the study. 
8.3. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the study but are not 
subsequently enrolled. An enrolled subject is defined as one for which appropriate written 
informed consent has been obtained, who meets all eligibility criteria and is randomized to 
receive study drug. Subjects who fail to meet entry criteria may be eligible to rescreen at a later 
time.  
8.4. 
Lifestyle Considerations 
Subjects must refrain from consuming alcohol for the duration of the study. 
CNS depressants in combination with lofexidine may increase the risk of hypotension and 
bradycardia. Subjects should be advised to be cautious prior to driving or operating heavy 
machinery if on concomitant CNS depressants during the study until they know how they react 
to study drug. 
8.5. 
Subject Discontinuation Criteria 
The Investigator or Sponsor may discontinue individual subjects from the study at any time if it 
is deemed clinically appropriate or for any reason, including the following: 
• Cardiovascular events 
− QTcF >500 msec or >25% above screening value for both males and females. 
− New onset of clinically significant abnormal electrocardiogram (eg, second- or 
third-degree heart block or uncontrolled arrhythmia, prolonged QTcF interval). 
− Persistent signs or symptoms of hypotension, bradycardia, or hypoperfusion. 


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− Single occurrence of symptomatic bradycardia (as assessed by the Investigator, 
regardless of blood pressure) associated with chest pain, shortness of breath, or 
decreased level of consciousness. 
− 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. 
• Evidence of repeated alcohol use (eg, 2 positive alcohol tests after Screening) during 
the study. Alcohol or other sedative/hypnotic withdrawal signs and symptoms 
developing following enrollment into the study. 
• More than 2 repeat occurrences of opioid rescue medication usage reported by the 
subject after Screening. 
• An intolerable AE or SAE; the relationship to study drug must be recorded in source. 
• Requirement for a treatment that is prohibited (Section 9.4) by the protocol. 
• Noncompliance with the protocol, including but not limited to showing evidence of 
illicit drug use while participating in the study or refusal or inability to continue 
opioid taper schedule per protocol.  
• Lost to follow up: If a subject is lost to follow-up, repeated attempts (defined as a 
minimum of 3 telephone calls, followed by sending a letter) will be made to reach the 
subject. If repeated attempts are unsuccessful, lost to follow up will be recorded in the 
subject's source document and electronic case report form (eCRF) as the reason for 
early discontinuation. 
• Withdrawal of consent: Subjects are free to withdraw from the study at any time, 
regardless of their reasons, and without prejudice to further treatment. In such cases, 
the subject will be asked about the reason(s) for the decision to withdraw consent and 
the reason(s) clearly documented in the subject's source document and eCRF. 
Subjects withdrawing consent will be asked to complete early discontinuation 
procedures but have the option to refuse. 
8.6. 
Early Discontinuation Visit 
If a subject is discontinued from the study before completion, regardless of whether they have 
received study drug, the reason for discontinuation must be documented in the subject’s source 
document and eCRF. Whenever a subject is discontinued, the procedures/assessments listed for 
the EOS Visit in the Schedule of Assessments (Table 2 or Table 3) should be performed. If a 
subject discontinues on a scheduled visit, assessments completed at that visit should be entered 
into the eCRF for that scheduled visit. Assessments required for the EOS Visit that are not 
required at the scheduled visit (eg, a complete physical examination, clinical laboratory tests) 
should be completed and entered into the eCRF for the EOS Visit. 


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Subjects who prematurely discontinue the study will be instructed to taper study drug as 
described in Section 9.2.3 and to complete the at-home assessments for the study drug taper 
period (Table 4 or Table 5). Once discontinued, subjects may not re-enter the study. 
8.6.1. 
Early Discontinuation Follow-up 
If a subject discontinues from the study, the subject will be contacted 30 days after the last day of 
study drug administration, unless the subject withdraws consent and refuses post-study contact. 
This telephone contact will be recorded in the source document. If a subject discontinues 
participation due to an AE/SAE that is at least possibly related to study drug, the subject will be 
followed until the event has resolved, stabilized or otherwise explained.  


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Randomization and Blinding 
9.1.1. 
Randomization 
Eligible subjects will be randomized in a 1:1 ratio to LUCEMYRA or placebo. The 
randomization will be stratified by total opioid dose, in MED, captured at Screening (<90 MED, 
≥90 MED). The subject’s baseline opioid use and changes to doses for planned taper reductions 
should be submitted to and approved by the Medical Monitor prior to Day -1. 
Subject randomization will be performed using a computer-generated randomization schedule, 
providing site staff with a randomization code linked to the study drug kit number to be used.  
Hard copies of the study drug randomization schedule will be stored securely. Only medically 
necessary unblinding(s) will be allowed. 
9.1.2. 
Maintaining and Breaking the Blind 
All subjects, study personnel (including the Investigator, study coordinator(s), 
pharmacist/designee), and the Sponsor will be blinded to the identity of the study drug (active or 
placebo) administered to subjects. 
An interim analysis will be conducted after approximately 30 subjects have completed or 
discontinued the study. For the interim analysis, the blind will be broken for the statistical 
programmers and Sponsor-designated reviewers. Unblinded results and individual subject 
treatment assignments will not be provided to subjects, Investigators, or other study personnel. 
If an Investigator believes it is necessary to break the blind for reasons of subject safety, the 
Investigator must call the Sponsor’s Medical Monitor (or designee) for consultation before 
unblinding. The decision to break the study blind should be made in cases of life-threatening 
emergency when knowledge of the treatment arm investigational agent will influence clinical 
management. If, after discussion with the Medical Monitor, it is determined that the study drug 
should be disclosed, medical personnel will be able to access this information via the 
randomization system. Circumstances surrounding unblinding of subjects must be documented in 
writing. Subject completion and withdrawal causality should be assessed by the Investigator 
before unblinding of treatment assignment but must not delay treatment in an emergency 
situation. The date and reason for the unblinding must be recorded in the subject’s source record. 
Contact information for the Sponsor’s Medical Monitor is as follows: 
9.2. 
Treatments Administered 
9.2.1. 
Multimodal Pain Management Plan 
Prior to randomization, the Investigator and subject should discuss and agree upon a multimodal 
pain management plan to be instituted during and after the opioid taper to help the subject 


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manage pain. A plan must be agreed upon and recorded prior to randomization; however, it can 
be updated throughout the study, as needed. Updates made to the plan should be recorded. 
Planned pharmacologic and non-pharmacologic treatments should be in compliance with 
Section 9.4. 
9.2.2. 
Study Drug Preparation 
No special preparation is required before dosing of study drug. 
9.2.3. 
Study Drug Administration  
Day 1 dosing with study drug will begin in the clinic as 1 tablet (LUCEMYRA 0.18 mg/tablet or 
matching placebo) QID for a total daily dose of LUCEMYRA 0.72 mg or matching placebo. 
Subjects will be instructed to take their study drug in the morning upon awakening and then 
every 5 to 6 hours thereafter. Doses should be taken 5 to 6 hours apart and no more than 4 times 
per day. At the Day 1 Visit (Visit 1), the Investigator should schedule a phone call with the 
subject, to occur prior to the second dose of study drug on Day 2, to review the subjects at-home 
vital signs measurement and how the subject is feeling. The subject will be instructed to contact 
the site if they experience signs or symptoms of hypotension, bradycardia, or orthostasis (eg, 
lightheadedness, slow heart rate, dizziness, feeling faint at rest or when standing up) while 
continuing to dose at home on Day 1. If the subject contacts the site on Day 1 reporting these 
symptoms, the Investigator should consider reducing the planned first daily dose on Day 2. 
On Day 2 the subject will be instructed to take 2 tablets QID (LUCEMYRA 1.44 mg/day or 
matching placebo), unless Day 1 dosing was not well-tolerated. The subject should contact the 
site if they experience signs or symptoms of hypotension, bradycardia, or orthostasis (eg, 
lightheadedness, slow heart rate, dizziness, feeling faint at rest or when standing up) after the 
first daily dose. The Investigator will contact the subject on Day 2, prior to the second dose of 
the day, to review the subject’s at-home vital signs measurement and how the subject is feeling. 
The Investigator should discuss with the subject any changes to dosing of study drug. Dosing 
instructions may include an increase to 3-tablets per dose due to subject report of intolerable 
opioid withdrawal symptoms, or a reduction back to 1 tablet per dose, due to intolerability of 
study drug. 
On Day 3 and beyond, dosing will be at the discretion of the Investigator, as guided by subject 
tolerability of study drug and opioid withdrawal symptoms. 
The dose of study drug may be increased to manage opioid withdrawal symptoms. If an 
increased dose of study drug is not well-tolerated, the dose can be decreased. A single dose of 
study drug should not exceed 4 tablets (LUCEMYRA 0.72 mg or matching placebo). The total 
daily dose of study drug should not exceed 4 tablets QID (LUCEMYRA 2.88 mg/day or 
matching placebo). 
Dosing of study drug will continue for 5 days after the last opioid dose. Study drug will then be 
tapered over an additional 4 days. The following schedule will be followed over the study drug 
taper period: 
• If taking 4 tablets QID (LUCEMYRA 2.88 mg/day or matching placebo) on fifth day 
after the last opioid dose 
− 3 tablets QID (LUCEMYRA 2.16 mg/day or matching placebo) for 1 day 


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− 2 tablets QID (LUCEMYRA 1.44 mg/day or matching placebo) for 2 days 
− 1 tablet QID (LUCEMYRA 0.72 mg/day or matching placebo) for 1 day 
− Study drug discontinued 
• If taking 3 tablets QID (LUCEMYRA 2.16 mg/day or matching placebo) on fifth day 
after the last opioid dose 
− 2 tablets QID (LUCEMYRA 1.44 mg/day or matching placebo) for 2 days 
− 1 tablet QID (LUCEMYRA 0.72 mg/day or matching placebo) for 2 days 
− Study drug discontinued 
• If taking 2 tablets QID (LUCEMYRA 1.44 mg/day or matching placebo) on fifth day 
after the last opioid dose 
− 1 tablet QID (LUCEMYRA 0.72 mg/day or matching placebo) for 2 days 
− 1 tablet twice daily (LUCEMYRA 0.36 mg/day or matching placebo) for 2 days 
− Study drug discontinued 
• If taking 1 tablet QID (LUCEMYRA 0.72 mg/day or matching placebo) on the fifth 
day after the last opioid dose 
− 1 tablet twice daily (LUCEMYRA 0.36 mg/day or matching placebo) for 4 days 
− Study drug discontinued 
9.3. 
Adjustment Criteria for Opioid Taper 
Subjects will be tapered from their baseline total daily dose of opioid (calculated as MED) over a 
14-day period. The opioid dose will be decreased as close as possible to achieve the following 
dose reduction targets: 50% from the baseline MED beginning with the last dose of the day on 
Day -1, an additional 25% of the baseline MED beginning with the first dose of the day on 
Day 6, and a final 25% of the baseline MED (to dose of zero) beginning with the first dose of the 
day on Day 13 (Figure 1). Reminders for opioid dose reduction may be done via phone, text, or 
other electronic message. 
Opioid dosing to achieve the required dose reductions in accordance with the protocol defined 
taper must be planned during Screening. Any changes in opioid prescription to facilitate the 
protocol taper should be discussed with the subject’s primary pain physician, when applicable, 
and prescribed in advance of randomization. The Investigator should work with a preferred 
pharmacy informed about the subject’s participation in a clinical trial in order to fulfill 
prescribing needs to facilitate the opioid taper. Opioid prescriptions should be written to 
accommodate the planned taper, based on the following considerations: 
• Subjects should be maintained on the same opioid molecule throughout the taper and 
not converted to new molecules.  
• Priority should be given to eliminating opioid medications for breakthrough pain as 
part of the first opioid dose reduction (50% of baseline MED) if possible. If not 
possible, dosing of opioid medications being taken for breakthrough pain should be 


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changed to be part of a fixed dose regimen appropriate to achieve the target MED 
reduction.  
• Opioid dose reductions should be as close as possible to the nominal reductions 
specified per protocol (ie, 50% or 25% reduction). Round up on the dose of the 
available opioid formulation if unable to adjust exactly to meet nominal MED 
reduction criteria. 
The subject’s baseline opioid regimen and MED calculation as well as the opioid regimen 
planned to achieve each taper step should be submitted to and approved by the Medical Monitor 
prior to Day -1. The Investigator will discuss and confirm the subject’s agreement to comply 
with the opioid dosing regimen for each opioid taper step based on the Medical Monitor-
approved plan. 
Non-opioid medications taken during the study should be in compliance with the allowed 
concomitant treatments in Section 9.4. Opioid dose reductions may not occur on a Friday or 
Saturday unless clinic can accommodate subjects on Saturday and Sunday. Qualified study 
personnel at the clinic should call the subject the day after the opioid dose is decreased (except 
on Day 1 since the subject will come to the clinic) to review the subject’s at-home vital signs 
measurement and how the subject is feeling. Upon review by the Investigator or designee, 
changes to dosing of study drug should also be discussed with the subject, if applicable. 
Subjects who experience intolerable withdrawal symptoms despite increasing their dose of study 
drug to the maximum tolerated dose (not to exceed 4 tablets QID) will be allowed to pause the 
opioid taper once. Pausing the opioid taper includes either a return to the last stable opioid dose 
for the remainder of the current opioid dose reduction period, or remaining on the current opioid 
dose instead of reducing at the next scheduled reduction, resulting in an overall extended opioid 
taper period and study duration. For example, if a subject experiences intolerable withdrawal at 
the second opioid dose reduction step [25% of baseline MED], they may either 1) return to the 
first reduction dose [50% of baseline MED]) or, 2) when the withdrawal persists until the next 
scheduled reduction step, they may remain for longer at the current opioid dose [25% of baseline 
MED]. In both cases, the taper must be resumed following the single pause in accordance with 
the protocol schedule. Subjects who cannot or are unwilling to continue the opioid taper after one 
pause will be discontinued from the study. 
Decisions on whether to pause the opioid taper will be based on subject request and an 
evaluation (in clinic or over the phone) of the subject’s status by the Investigator. Subjects may 
request to pause the opioid taper due to opioid withdrawal symptoms. If the subject’s last COWS 
score is ≥5 OR if based on i) the Investigator’s discussion with the subject, ii) review of ongoing 
subject-reported withdrawal related AEs, and iii) most recent scores for subject reported 
withdrawal scales, the subject’s desire to pause the taper is related primarily to opioid 
withdrawal discomfort in the Investigator’s opinion, then the taper may be paused. In the event 
that the Investigator assesses the subject’s desire to pause the taper to be primarily related to 
pain, a taper pause will not be permitted; however, if the subject is willing to continue the per 
protocol taper, recommended modifications to their concurrent pain management plan should be 
discussed and recorded. Subjects unwilling to continue the per protocol taper and not experiencing 
opioid withdrawal to permit a single pause should be discontinued from the study. 


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Study drug dosing for an opioid taper pause will remain at the discretion of the Investigator, as 
guided by subject tolerability of study drug and opioid withdrawal symptoms. The dose of study 
drug can be increased or decreased as needed. 
9.4. 
Prior and Concomitant Treatments 
Prior treatments are defined as treatments taken within 30 days before randomization, regardless 
if usage continues after randomization. Concomitant treatments are defined as treatments taken 
after randomization. 
Prior treatments will be documented on the eCRF. The reported treatments will be reviewed and 
approved by the Investigator/study physician/assigned staff for entry into the study.  
All concomitant treatments will be recorded in subject diaries and on the eCRF along with dose, 
dates of administration, and reason for use. 
9.4.1. 
Prohibited Treatments 
The following treatments are not allowed within 30 days prior to Screening or throughout the 
study: 
• Alpha-2 adrenergic agonists 
• Antiarrhythmics 
• Barbiturates 
• Paraldehyde 
• Stiripentol 
• Psychoactive herbal preparations (including St. John’s Wort, Kratom, cannabis, and 
products containing cannabinoids) 
• Aspirin (baby aspirin permitted if taking prior to study for prophylactic purposes) 
9.4.2. 
Permitted Treatments 
Medications taken for stable hypertension are permitted when dose/regimen has been consistent 
for a minimum of 3 months prior to screening. 
Strong cytochrome P450-2D6 inhibitors, muscle relaxants, benzodiazepines, hypnotics, 
soporifics, tricyclic antidepressants, selective serotonin reuptake inhibitors, permitted 
anticonvulsants (including but not limited to gabapentin and pregabalin) and medications given 
for stable neuro-psychiatric diagnoses at a consistent dose/regimen for at least 30 days prior to 
randomization are permitted in accordance with exclusion criterion 14. These medications must 
be continued at the same dose/regimen for the duration of the study drug administration period. 
In the event the subject reports new regular or chronic use of any of the above-mentioned 
medication (whether over-the-counter or prescription), eligibility to continue in the study must 
be evaluated in consultation with the Medical Monitor. 
CNS depressants in combination with lofexidine may increase the risk of hypotension and 
bradycardia. Subjects should be advised to be cautious prior to driving or operating heavy 


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machinery if on concomitant benzodiazepines during the study until they know how they react to 
study drug. 
Other concomitant treatments are permitted throughout the study, as clinically warranted, for the 
treatment of symptoms related to opioid withdrawal. The following treatments may be used in 
this study as appropriate: 
• Guaifenesin (for cough). 
• Alumina, magnesia, and simethicone (for emesis and nausea) 
• Dioctyl sodium sulfosuccinate and psyllium hydrocolloid suspension (for 
constipation) 
• Bismuth sulfate (Pepto-Bismol®) (for diarrhea) 
• Diphenhydramine, melatonin and zolpidem (for insomnia) 
Subjects taking a prescribed medication for opioid-induced constipation (OIC) prior to Screening 
may continue to use the medication on an as needed basis. Subjects should be advised to 
consider avoiding use of OIC medications during the opioid taper to not exacerbate withdrawal-
induced diarrhea.  
Use of concomitant treatments to treat withdrawal symptoms will be recorded daily by subjects 
using the diary. 
Subjects experiencing pain requiring medication will be allowed to use the following treatments: 
• Acetaminophen (up to 4 g per day, dispensed as 500-mg tablets). Subjects receiving 
acetaminophen-containing opioid products should not receive acetaminophen as part of 
their pain management plan. 
• Nonsteroidal anti-inflammatory drugs provided dosing is within product label 
recommendations 
• Non-opioid topical treatments (compounded or non-compounded) 
• Non-prescription medications that are often taken to treat pain, depression and anxiety 
(excluding St. John’s Wort, Kratom, cannabis and products containing cannabinoids) 
• Non-pharmacologic modalities/interventions (eg, physical therapy, psychotherapy, 
hypnosis, acupuncture, massage, chiropracty, ice packs, moist or dry heat, etc) 
Use of opioid medication as a rescue for breakthrough pain should be strongly discouraged. 
Subjects experiencing intolerable pain during the study should be instructed to call the site to 
discuss further modifications to their non-opioid pain management plan. Subject reported use of 
any opioid rescue medication should be recorded and discussed by the Investigator and Medical 
Monitor to assess eligibility to continue in the study and will include a review of safety concerns, 
impact on effectiveness measures, and consistency with required MED-percent reduction targets. 
More than 2 repeat occurrences of opioid rescue medication usage reported by the subject will 
require study discontinuation.  
Use of any medication or non-pharmacologic intervention or treatment for pain will be recorded 
daily by subjects using the diary. 


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9.5. 
Treatment Compliance 
Self-dosing compliance will be evaluated at each clinic visit by pill count and subject’s diary 
report of dosing. Subjects will be instructed to call the Investigator’s office before taking the next 
dose of study drug if they notice any symptoms of hypotension, bradycardia, and/or orthostasis, 
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 in source documents and confirmed also by pill 
count and subject report at the next visit. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
10.1.1. 
Lofexidine Hydrochloride 
Lofexidine hydrochloride (HCl) tablets contain lofexidine, which is a selective adrenergic α2 
receptor agonist, as the HCl salt. Lofexidine HCl is chemically designated as 2-[1-(2,6-
dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride with a molecular formula 
of C11H12Cl2N2O•HCl. Its molecular weight is 295.6 and its structural formula is: 
 
The description of the study drug is presented in Table 8. 
Table 8: 
Investigational Product 
 
Investigational Product 
Product Name: 
Lofexidine HCl (LUCEMYRA™) 
Dosage Form: 
Tablet 
Unit Dose: 
Each LUCEMYRA tablet is 0.18 mg. See Section 9.2.3 for dose adjustments and 
taper regimens. 
Route of Administration: 
Oral 
Physical Description: 
Lofexidine HCl is a synthetic product and has the chemical designation of  
2 [1-(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride. 
Lofexidine HCl will be supplied in peach-colored tablets containing 0.18 mg of 
active medication for oral administration. 
Manufacturer: 
 
 
HCl = hydrochloride; 
 QID = 4 times daily 
10.1.2. 
Placebo 
Placebo tablets will be identical in appearance to LUCEMYRA tablets. 


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10.2. 
Study Drug Packaging and Labeling 
The study drug will be packaged in bottles of 112 tablets. The package product label will include 
the following information: 
• Sponsor’s name 
• Protocol number 
• A unique package number for purposes of study drug accountability 
• A description of the study drug (ie, “Lofexidine or Placebo”) 
• Statement that the study drug is for investigational use only 
10.3. 
Study Drug Storage 
Lofexidine HCl and placebo should be stored in the original package at controlled room 
temperature 20 to 25°C (68 to 77°F), with excursions permitted between 15 to 30°C (59 to 86°F). 
10.4. 
Study Drug Preparation 
See Section 9.2.2. 
10.5. 
Administration 
See Section 9.2.3. 
10.6. 
Study Drug Accountability 
All study drug required for completion of this study will be provided by the Sponsor. Accurate 
recording of all study drug received, dispensed, administered, and returned will be maintained by 
study site personnel. All study drug is to be used only as described by this study protocol by 
appropriately licensed Investigators named in Form FDA 1572. 
Study staff should retain the original individual containers, including those empty, partially 
empty, or full. Study drug must be inventoried. If any study drug is lost or damaged, its 
disposition should be documented. Unused study drug will be retained at the participating sites to 
enable a full study drug inventory by the sites’ respective monitors
 
 
 
10.7. 
Study Drug Handling and Disposal 
At the end of the study, all unused study drug must be inventoried. If any study drug is lost or 
damaged, its disposition should be documented. Unused study drug will be retained at the 
participating sites pending instructions for disposition by the Sponsor at the end of the study. 


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11. 
ASSESSMENTS OF EFFECTIVENESS 
11.1. 
Numeric Rating Scale (NRS) of Pain Intensity 
The NRS of pain intensity is a unidimensional, segmented numeric version of the visual analog 
scale. A subject selects a whole number (0 to 10) that best indicates the intensity of his/her pain. 
The format consists of a horizontal line which is anchored by terms defining pain levels where 
0 represents no pain and 10 represents worst pain imaginable. 
At bedtime, subjects will answer the following questions regarding daily pain intensity: 
How would you rate the average pain due to your current chronic pain condition over the last 
24 hours? 
How would you rate the worst pain due to your current chronic pain condition over the last 
24 hours? 
Sometimes when people come off opioids, they feel aches and pains all over their body. How 
would you rate the average pain, all over your body over the last 24 hours? 
Sometimes when people come off opioids, they feel aches and pains all over their body. How 
would you rate the worst pain, all over your body over the last 24 hours? 
NRS chronic pain scales will be completed daily at home before bedtime beginning at Screening 
through the 30-day follow-up phone call and at clinic visits (and Early Termination, if 
applicable). NRS all over body pain scales will be completed at home before bedtime beginning 
on Day 1 through the EOS Visit and at clinic visits (and Early Termination, if applicable). NRS 
scales completed at the Day 1 Visit (Visit 1) should be completed prior to the first dose of study 
drug. 
A copy of the NRS is provided in Section 16.1. 
11.2. 
Clinical Opiate Withdrawal Scale (COWS) 
The COWS will be used to assess effectiveness of LUCEMYRA in alleviation of opioid 
withdrawal [Wesson 2003]. The COWS is a clinician-administered instrument that rates 
11 common opioid withdrawal signs and symptoms. These include: resting pulse rate; sweating; 
restlessness; pupil size; bone or joint aches; runny nose or tearing; gastrointestinal upset; tremor; 
yawning; anxiety or irritability; and gooseflesh skin. Lower total scores indicate a more positive 
clinical outcome. 
The COWS completed at the Day 1 Visit (Visit 1) should be completed prior to the first dose of 
study drug.  
A copy of the COWS assessment tool is provided in Section 16.4. 
11.3. 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) 
The SOWS-Gossop scale assesses subjective symptoms of opioid withdrawal [Vernon 2016, 
Gossop 1990]. 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) 
(Table 9). The overall score is the simple sum of the 10 item scores. Lower observed values in 


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SOWS-Gossop scores indicate a more positive clinical outcome. The SOWS-Gossop will be 
completed daily beginning at Day 1 at home at bedtime and at clinic visits (and Early 
Termination, if applicable). The SOWS-Gossop completed at the Day 1 Visit (Visit 1) should be 
completed prior to the first dose of study drug. 
Table 9: 
SOWS-Gossop Scoring Method 
 
Score 
Condition 
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/problem sleeping 
0 
1 
2 
3 
SOWS-Gossop = Short Opiate Withdrawal Scale of Gossop 
Note: possible score range is 0 to 30. 
A copy of the SOWS-Gossop is provided in Section 16.5. 
11.4. 
Subjective Opiate Withdrawal Scale of Handelsman (SOWS-H) 
The SOWS-H scale assesses subjective symptoms of opioid withdrawal [Handelsman 1987]. It is 
a subject-rated scale consisting of 19 items that are scored on a 5-point scale of 0 = not at all, 
1 = a little, 2 = moderately, 3 = quite a bit, and 4 = extremely. The overall score is the simple 
sum of the 19 item scores. Lower observed values in SOWS-H scores indicate a more positive 
clinical outcome. The SOWS-H will be completed daily beginning at Day 1 at home at bedtime 
and at clinic visits (and Early Termination, if applicable). The SOWS-H completed at the Day 1 
Visit (Visit 1) should be completed prior to the first dose of study drug.  
Item 16 of the SOWS-H was rephrased to be more appropriate for this population [FDA 2014]. 
A copy of the SOWS-H is provided in Section 16.6. 
11.5. 
Hospital Anxiety and Depression Scale (HADS) 
The HADS is a self-reported screening tool for anxiety and depression in nonpsychiatric clinical 
populations. The scale consists of 14 items (7 each for anxiety and depression), each rated on a 
4-point scale. Responses are based on the relative frequency of symptoms over the preceding 
week. Possible scores range from 0 to 21 for each subscale. An analysis of scores on the 
2 subscales supported the differentiation of each mood state into 4 ranges: non-cases (scores 0 to 


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7), mild cases (scores 8 to 10), moderate cases (scores 11 to 15), and severe cases (scores 16 or 
higher) [Zigmond 1983]. 
A copy of the HADS is provided in Section 16.7. 
11.6. 
Insomnia Severity Index (ISI) 
The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of 
insomnia. The recall period is the last 2 weeks and the dimensions evaluated are: severity of 
sleep onset, sleep maintenance and early morning awakening problems, sleep dissatisfaction, 
interference of sleep difficulties with daytime functioning, noticeability of sleep problems by 
others, and distress caused by the sleep difficulties. A 5-point Likert scale is used to rate each 
item, yielding a total score ranging from 0 to 28. The total score is interpreted as follows: 
absence of insomnia (0–7); sub-threshold insomnia (8-14); moderate insomnia (15–21); and 
severe insomnia (22–28) [Bastien 2001]. 
A copy of the ISI is provided in Section 16.8. 
11.7. 
Modified Clinical Global Impression – Subject Version (MCGI-S) 
The MCGI-S includes 2 items: 
• A 7-point scale that allows subjects to rate the severity of opiate withdrawal 
symptoms.  
• A 4-point scale that allows subjects to rate the degree of side effects from their study 
drug. 
The MCGI-S will be completed once daily beginning at Day 1 at home at bedtime and at clinic 
visits (and Early Termination, if applicable).  
A copy of the MCGI-S is provided in Section 16.9. 
11.8. 
Modified Clinical Global Impression – Rater Version (MCGI-R) 
The MCGI-R includes 2 items: 
• A 7-point scale that allows clinicians to rate the severity of a subject’s opiate 
withdrawal symptoms.  
• A 4-point scale that allows clinicians to rate the degree of a subject’s side effects 
from study drug. 
A copy of the MCGI-R is provided in Section 16.10. 
11.9. 
EuroQol 5-Dimension 5-Level (EQ-5D-5L) 
The EQ-5D-5L is a health state utility instrument that evaluates preference for health status 
(utility). The 5 items in the EQ-5D-5L comprise 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) each of which are rated on 5 levels of 
severity. Responses to the 5 items encode a discrete health state which is mapped to a preference 
(utility) specific for different societies. Subjects also rate their perception of their overall health 
on a separate visual analogue scale.  


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A copy of the EQ-5D-5L is provided in Section 16.11. 
11.10. 
Short Form Health Survey – 36 Items (SF-36) 
The SF-36 assesses 8 health concepts: physical functioning, bodily pain, role limitations due to 
physical health problems, role limitations due to personal or emotional problems, emotional 
well-being, social functioning, energy/fatigue, and general health perceptions. It also includes a 
single item that provides an indication of perceived change in health. 
A copy of the SF-36 is provided in Section 16.12. 
11.11. 
Subject Satisfaction Questionnaire 
Subject satisfaction will be scored from 0 (very satisfied) to 4 (very dissatisfied) based on the 
following question: Overall, how would you rate your satisfaction with the treatment you 
received in this study to help you discontinue using your opioid? 
0 = very satisfied 
1 = satisfied 
2 = neither satisfied nor dissatisfied 
3 = dissatisfied 
4 = very dissatisfied 
A copy of the Subject Satisfaction questionnaire is provided in Section 16.13. 
11.12. 
Subject Interview 
The primary purpose of the qualitative interview is to provide additional data to augment the data 
collected from quantitative instruments to assess withdrawal, pain intensity, quality of life, 
treatment satisfaction, and others. The results of this interview will provide information that may 
be useful for planning future studies to evaluate the safety and efficacy of LUCEMYRA in the 
setting of an opioid taper in subjects with chronic non-cancer pain. The interview will be 
conducted via a centralized interviewer through a phone call. The interview should take place no 
more than 5 days after the EOS Visit. 
The qualitative interview will be designed to collect information about: (1) subjects’ experiences 
with opioid withdrawal syndrome while gradually tapering their opioids and the relevance, 
utility, and interpretability of the opioid withdrawal scales used in the study to assess their opioid 
withdrawal symptoms; (2) factors that may facilitate or interfere with subject recruitment and 
retention in a large clinical trial for the discontinuation of opioid therapy; (3) subjects’ 
experiences in the clinical trial, including questions about how they would improve the 
experience and whether they would participate in future trials; and (4) subjects’ experiences and 
preferences regarding the treatments administered in the clinical trial. Questions will be 
organized from more general (open-ended) to more specific. 
Audio from each interview will be recorded. 


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12. 
ASSESSMENTS OF SAFETY 
Safety assessments will be performed at the time points outlined in Table 2, Table 3 and Table 4. 
12.1. 
Safety Parameters 
12.1.1. 
Demographic/Medical History 
The medical history will include demographic information, current co-morbidities, relevant past 
illnesses, and surgical procedures performed within the prior 6 months. Assessments will also 
include characterization of the subject’s baseline pain state, condition, opioid use, and opioid 
withdrawal history. 
12.1.2. 
Vital Signs 
Orthostatic vital signs will be measured in-clinic. Orthostatic vital signs will be measured first 
after the subject has been sitting for at least 5 minutes (systolic/diastolic blood pressure, pulse, 
and temperature) and then after the subject has been standing for at least 3 minutes 
(systolic/diastolic blood pressure and pulse). On Day 1, orthostatic vital signs should be assessed 
pre-dose and 1-hour post-dose of study drug. A post-dose assessment is not required after Day 1. 
When repeat vital signs are performed, temperature does not need to be collected (only 
systolic/diastolic blood pressure and pulse). 
Resting vital signs (systolic/diastolic blood pressure and pulse) only will be measured at home 
using a vital sign monitor during phone calls after dose reductions, and every day during the 
4-day study drug taper through the EOS Visit. Resting vital signs will be measured after the 
subject has been sitting quietly for at least 5 minutes and, during the study drug taper and after, 
will be taken twice daily, once in the morning and once in the evening.  
Subjects should contact the Investigator if they experience signs or symptoms of hypotension, 
bradycardia, or orthostasis (eg, lightheadedness, slow heart rate, dizziness, feeling faint at rest or 
when standing up) or hypertension (eg, pounding headache, dizziness, palpitations). Subjects 
should contact the Investigator if they record an at-home vital signs measurement reaching or 
exceeding a systolic blood pressure of ≥180 mmHg, diastolic blood pressure ≥105 mmHg, or 
heart rate of ≥120 bpm. Symptomatic episodes of hypotension should be captured as an AE. 
Confirmed instances of meeting criteria for hypertension should be captured as AEs regardless of 
symptomology. 
During phone calls, the Investigator should ask the subject for a vital sign measurement and 
review subject-measured at-home vital signs. 
Blood pressure and pulse measurements taken in-clinic or at-home should be repeated after a 
15-30 minute rest if they meet the following criteria:  
• Hypertension: systolic blood pressure of ≥180 mmHg, diastolic blood pressure ≥105 
mmHg, or heart rate of ≥120 bpm 
• Hypotension: systolic blood pressure of ≤90 or a diastolic blood pressure of ≤60, and 
a heart rate <50 bpm 


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If the subject has a confirmed systolic blood pressure of ≥180 mmHg, diastolic blood pressure 
≥105 mmHg, or heart rate of ≥120 bpm, and is symptomatic, the subject should be seen 
(preferably by the Investigator). 
If the subject has a confirmed systolic blood pressure of ≤90 or a diastolic blood pressure of ≤60, 
and a heart rate <50 bpm, and is symptomatic, the Investigator should advise the subject to either 
decrease or hold the next dose of study drug. 
12.1.3. 
Weight and Height 
For measuring weight, a scale with appropriate range and resolution will be used and must be 
placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and jackets 
so that only light clothing remains. They must also remove the contents of their pockets and 
remain still during measurement of weight.  
Height will be measured without shoes. 
12.1.4. 
Physical Examination 
Physical examinations will be performed by the Investigator or qualified designee. A complete 
physical examination will include 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. A brief 
physical examination will consist of cardiac and pulmonary auscultation. 
The individual performing the physical examination will characterize findings as either normal 
or abnormal. Clinically significant abnormal physical examination findings found during 
Screening should be reported on the medical history eCRF. Clinically significant abnormal 
physical examination findings found after the subject has received study drug will be reported as 
AEs on the eCRF. 
12.1.5. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS measures both suicidal ideation and suicidal behavior. When administered, all 
responses recorded on the scale must be provided by the subject either verbally or by gesture. 
The Baseline version of the C-SSRS (Section 16.2) will be used during Screening to assess 
lifetime suicidality. At all other protocol-specified time points, the C-SSRS – Since Last Visit 
version (Section 16.3) will be used to assess the subject’s suicidality since the last assessment. 
Any changes from baseline assessment should be reported as an AE on the eCRF. 
If any item(s) on the C-SSRS are answered with “yes”, a physician Investigator must review the 
subject’s responses in order to determine the subject’s study eligibility, or continued 
participation, and potential need for referral to a mental health professional. A significant risk of 
suicide is defined as a “yes” in answer to: a) questions 4 or 5 on the suicidal ideation section, or 
b) any questions on any item in the suicidal behavior section. This must be reported as an SAE 
and followed up accordingly. Additionally, if a subject responds “yes” to any of the suicidal 
ideation questions 1 to 3, the Investigator should apply clinical judgment to determine the need 
for reporting as an AE or SAE and the need for any referral. 


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12.1.6. 
Electrocardiogram 
Standard 12-lead electrocardiograms will be performed. Electrocardiograms should be performed 
before blood draws and after the subject has rested quietly for at least 10 minutes in a supine 
position. The Investigator (or Investigator’s designee who is a physician) will interpret the 
electrocardiogram and will record his/her global interpretation of the electrocardiogram (ie, 
normal or abnormal) on the tracing. Each electrocardiogram tracing must also include the 
signature of the Investigator and the date that the electrocardiogram was interpreted. If the global 
interpretation is abnormal, the Investigator will indicate on the tracing whether the abnormality is 
clinically significant or not clinically significant. Clinically significant electrocardiograms should 
be repeated up to 2 times after another rest of at least 10 minutes. A copy of each 
electrocardiogram and the physician’s assessment will be filed with the source documents. 
During the study, when any QTcF interval is ≥495 msec, 2 additional electrocardiograms should 
be taken at 10- to 15-minute intervals (electrocardiograms should be done after the subject has 
been resting for at least 10 min). The QTcF interval on all electrocardiograms should be 
confirmed by the Investigator. If it is determined that 2 of the 3 QTcF intervals exceed 500 msec 
or >25% above screening value, then the subject will be discontinued from the study. 
12.1.7. 
Laboratory Assessments 
See Table 10 for the list of clinical laboratory tests to be performed. Additional tests may be 
performed at any time during the study as determined necessary by the Investigator or required 
by local regulations. All study-required laboratory assessments will be performed by a central 
laboratory.  
The Investigator must review the laboratory report and document this review. The laboratory 
reports must be filed with the source documents. Clinically relevant changes during the study 
that result in changes in study drug, study participation, or concomitant treatment use will be 
recorded as AEs on the eCRF. Clinically significant abnormal laboratory findings are those 
which are not associated with the underlying disease, unless judged by the Investigator to be 
more severe than expected for the subject's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or medical monitor. If such values do not 
return to normal/baseline within a period of time judged reasonable by the Investigator, the 
etiology should be identified, and the Sponsor notified. 
All testing for opioids in the urine is qualitative, including confirmatory testing. Qualitative 
results will be reported for opioids by class with dipstick tests and by opioid analyte for urine 
specimens sent to the Sponsor’s central laboratory. No quantitative testing for opioids will be 
performed or reported throughout the study. 
All protocol-required laboratory assessments must be conducted in accordance with the 
laboratory manual.  


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Table 10: 
Clinical Laboratory Tests 
Hematologya 
Chemistryb 
Urinalysis 
Hemoglobin 
Cholesterol 
Color 
Hematocrit 
Triglycerides 
Clarity 
Red blood cells 
Sodium 
pH 
Mean corpuscular volume 
Potassium 
Specific gravity 
Mean corpuscular hemoglobin 
Chloride 
Protein 
Mean corpuscular hemoglobin concentration 
Carbon dioxide 
Glucose 
Red blood cell distribution width 
Glucose 
Ketones 
White blood cell count 
Creatinine 
Bilirubin 
Neutrophils 
Albumin 
Nitrite 
Lymphocytes 
Total protein 
Blood 
Monocytes 
Calcium 
Urobilinogen 
Eosinophils 
Phosphorus 
White blood cell count 
Basophils 
Aspartate aminotransferase 
Red blood cell count 
Platelet count 
Alanine aminotransferase 
Epithelial cells 
Prothrombin time 
Gamma-glutamyl transpeptidase Bacteria 
Activated partial thromboplastin time 
Total bilirubin 
Casts 
 
Lactate dehydrogenase 
Crystals 
 
Alkaline phosphatase 
Leukocyte esterase 
 
Blood urea nitrogen 
 
 
Thyroid-stimulating hormone 
 
 
Free thyroxine 
 
a Blood will be collected in anticoagulant containing evacuated venous blood collection tubes (eg, Vacutainer™). 
b Blood will be collected in serum separation evacuated venous blood collection tubes (eg, Vacutainer™) and serum 
separated according to standard procedures. 
Urine testing will be done for ethyl glucuronide, a metabolite of ethanol that is stable in urine 
and detectable up to 3 days after ingestion of alcohol. The first positive test for alcohol during 
the study should prompt subject counseling about the important in abstaining from alcohol use 
during the study. More than 2 positive tests for alcohol after Screening will require 
discontinuation from the study.  
Qualitative urine drug screening for illicit use will be performed at Screening for all subjects and 
at every clinic visit for the following drugs: amphetamines/methamphetamines, cocaine, 
barbiturates, opiates, benzodiazepines, cannabinoids, methadone, and buprenorphine. The central 
lab will provide standard sets of urine drug screen “dipsticks” for use across all sites. 
Quantitative confirmatory testing for illicit substances may be performed when results contradict 
subject self-report. Confirmed evidence of use of illicit substances will require discontinuation 
from the study. 
A urine pregnancy test designed to measure human chorionic gonadotropin will be performed for 
all female subjects, regardless of childbearing potential. 


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12.1.7.1. Evaluation of Treatment-emergent Elevated Liver Function Tests 
The following assessments should be performed in the event one of the following laboratory 
results occurs after study drug administration: 
• ALT >3 × ULN OR  
• AST >3 × ULN OR 
• Total bilirubin >2 × ULN 
1. Review of medical history and concomitant treatment or drug use. 
In this study of opioid withdrawal symptoms during opioid dose tapering, the occurrence of 
significant hepatic injury is most likely to arise from etiologies that are extraneous to the 
treatment protocol. Study subjects, though voluntarily seeking reduction or cessation of chronic 
opioid treatment, are known to have both physiological as well as psychologic responses to large 
reductions in opioid dose. These responses may include maladaptive behaviors that can result in 
hepatotoxic outcomes; thus, initial medical history and laboratory investigation should focus on 
whether any of the following has occurred: 
• Hepatoxic doses of acetaminophen with or without co-consumption of alcohol 
Note: If the medical history confirms high dose acetaminophen use, immediately refer the 
subject to a hospital emergency room where a serum tox screen should be performed that 
includes acetaminophen levels. Acetaminophen toxicity can be subtle yet does respond to 
acute intervention. 
• Hepatic injury due to acute binge alcohol consumption 
• Acute hepatitis due to viral transmission from the unsterile injection of illegally 
obtained narcotics 
• Hepatoxicity arising from the compensatory use of legal or illegal herbal supplements 
taken to address opioid withdrawal syndrome 
2. Assess for symptoms and perform repeat laboratory tests within 48-72 hours. 
Determine if subject is symptomatic (ie, assess for nausea, vomiting, anorexia, abdominal pain, 
or fatigue) and perform repeat testing (including ALT, AST, international normalized ratio, total 
and direct bilirubin, viral hepatitis panel, a urine drug screen, and if necessary, urine test for ethyl 
glucuronide) within 48-72 hours. A urine test for ethyl glucuronide is needed as part of repeat 
laboratory testing if alcohol use is suspected (ie, necessary if Visit 4 urine test results for ethyl 
glucuronide showed presence of the metabolite in the urine). 
If symptoms persist OR repeat testing shows either of the following, initiate close observation 
follow-up plan: 
• ALT and/or AST >3 × ULN for subjects with normal baseline measures OR  
• ALT and/or AST of a 2-fold increase above baseline values for subjects with elevated 
values before study drug exposure. 
3. Develop and implement a close observation follow-up plan (if applicable). 


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A close observation follow-up plan should be determined as appropriate for the subject by the 
Investigator in consultation with the Medical Monitor. Close observation procedures include, but 
are not limited to, the following: 
• Repeating liver enzyme and serum bilirubin tests 2-3 times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or the trial drug 
has been discontinued and the subject is asymptomatic. 
• Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• In the absence of an etiology, consider evaluating for autoimmune or alcoholic 
hepatitis, nonalcoholic steatohepatitis, hypoxic/ischemic hepatopathy, and biliary 
tract disease. 
• Obtaining a history of exposure to environmental chemical agents. 
• Considering gastroenterology or hepatology consultations. 
All subjects meeting criteria for elevated liver function tests following study drug administration 
should be followed until all abnormalities return to normal or to the baseline state. 
4. Discontinuation from study drug with safety follow-up through EOS period or until AE 
has resolved. 
Subjects should be discontinued from the study drug if:  
• ALT or AST >5 × ULN in 2 consecutive tests. 
• ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
12.2. 
Adverse and Serious Adverse Events 
AEs will be assessed by asking the subject, “How have you been feeling since I saw you last?” 
The study physician will review current AEs with the subject and assess any AEs unresolved 
from the previous visit. The type of AE, whether serious or non-serious, severity, and the 
relationship to study drug will be recorded by the physician in the subject’s source document and 
eCRF after each AE assessment. The physician’s clinical judgment will be used to assess the 
severity and relatedness of each AE. 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a subject participating in a clinical study. An AE 
includes any noxious, pathologic, or unintended change in anatomic, physiologic, or metabolic 
functions as indicated by physical signs, symptoms and/or laboratory changes. An unexpected 
AE is an AE not identified in nature, severity, or frequency in the current package insert for 
LUCEMYRA [USWM 2018]. 
Anticipated fluctuations of pre-existing conditions that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. Study events occurring after signing 


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informed consent, but prior to study drug administration, are to be documented in the subject’s 
medical history source and eCRF.  
For any pain-related AE, the subject will be questioned regarding changes since pre-study pain. 
12.2.1.2. Serious Adverse Event 
An SAE is defined as an AE meeting any of the criteria, in the view of either the Investigator or 
Sponsor, in Table 11. 


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Table 11: 
Definition of Serious Adverse Event 
Serious Adverse Event Criterion 
Guidance 
Results in death 
Any event resulting in a fatal outcome must be fully documented and 
reported, including deaths occurring within 4 weeks after the treatment 
ends and irrespective of the causal relationship to the investigational 
product. The death of a subject enrolled in a study is per se not an event, 
but an outcome. 
Is life-threatening 
The term life-threatening refers to an adverse event in which the subject 
was at immediate risk of death at the time of the event. It does not refer to 
an event, which may have caused death if it were more severe. 
Requires in-patient hospitalization or 
prolongation of existing hospitalization 
The term hospitalization means that the subject was admitted to hospital 
or that existing hospitalization was extended as a result of an event. 
Hospitalization describes a period of at least 24 hours. Overnight stay for 
observation, stay at emergency room, or treatment on an outpatient basis 
do not constitute a hospitalization. However, medical judgment must 
always be exercised and when in doubt the case should be considered 
serious (ie, if case fulfills the criterion for a medically important event). 
Hospitalizations for administrative or social purposes do not constitute a 
serious adverse event. Hospital admissions and/or surgical operations 
planned before study inclusion are not considered adverse events, if the 
illness or disease existed before the subject was enrolled in the study, 
provided that the condition did not deteriorate during the study. 
Results in persistent or significant 
disability/incapacity or substantial 
disruption of the ability to conduct 
normal life functions 
Disability/incapacity means a substantial disruption of a person’s ability 
to conduct normal life functions. In doubt, the decision should be left to 
medical judgment by the Investigator. 
Is a congenital anomaly/birth defect 
Congenital anomaly/birth defect observed in any offspring of the subject 
conceived during treatment with the investigational product. 
Is an important medical event 
Important medical events are events that may not be immediately life 
threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definition above. Examples of important 
medical events include adverse events that suggest a significant hazard, 
contraindication or precaution, occurrence of malignancy or development 
of drug dependency or drug abuse. Medical and scientific judgment 
should be exercised in deciding whether events qualify as medically 
important. 
12.2.2. 
Relationship of Adverse Event to Study Drug 
For each AE, the Investigator must assess the attribution of the study drug to the AE and 
determine whether the AE is or is not related to the study or test drug as defined below. When in 
doubt, the AE should be considered at least “possibly related” until further evidence becomes 
available to refute this assessment. 
Definitely Not Related 
Subject did not receive the test drug, the temporal sequence of the AE onset relative to 
administration of the test drug is not reasonable, or there is another obvious cause of the AE. 


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Possibly Related 
There is evidence of exposure to the test drug, the temporal sequence of the AE onset relative to 
administration of the test drug is reasonable, but the AE could have been due to another equally 
likely cause. 
Probably Related 
There is evidence of exposure to the test drug, the temporal sequence of the AE onset relative to 
administration of the test drug is reasonable, and the AE is more likely explained by the test drug 
than by any other cause. 
Definitely Related 
There is evidence of exposure to the test drug, the temporal sequence of the AE onset relative to 
administration of the test drug is reasonable, and the AE is more likely explained by the test drug 
than by any other cause, and the AE shows a pattern consistent with previous knowledge of the 
test drug or test drug class. 
12.2.3. 
Recording Adverse Events 
All AEs and details for the events will be recorded in the subject’s source document and eCRF. 
An AE should be documented in terms of a medical diagnosis and reported in standard medical 
terminology when possible. When this is not possible, the AE should be documented in terms of 
signs and/or symptoms observed or reported. It is important for the Investigator to only record 1 
AE per line on the eCRF. Combination events (eg, nausea/vomiting), should be entered as 2 
events.  
The Investigator must determine the intensity of the AE as defined by:  
• Mild: no medical interventions required, short lasting discomfort, and does not 
interfere with subject’s daily activities 
• Moderate: activity may be limited, and subject may require minimal medical therapy, 
intervention, or assistance 
• Severe: definitely limits subject’s daily activity that may require hospitalization and 
or intervention/therapy assess whether or not the study drug caused the AE 
The Investigator will record whether the AE or AEs led to discontinuation of the subject from the 
study, record the outcome of the AE (unresolved, resolved, resolved with sequelae, death, or 
unknown), and determine if the AE is serious. 
For this study, AEs and SAEs will be collected beginning with the start of dosing on Day 1 and 
will end 30 days after the last dose of study drug.  
12.2.4. 
Follow-up of Adverse Events 
The clinical course of each AE should be followed until resolution, stabilization, or until it has 
been determined that the study drug or participation is not the cause. The Investigator must 
provide the Sponsor with all relevant follow-up information necessary to facilitate a thorough 
understanding of the event and judgment regarding the relationship to the study drug or placebo. 
If a subject discontinues participation due to an AE/SAE that is at least possibly related to study 


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drug, the subject will be followed until the event has resolved, stabilized, or otherwise explained. 
This telephone contact will be documented in source. 
12.2.5. 
Expedited Reporting of Events 
12.2.5.1. Events Requiring Expedited Reporting to 
 
The following events should be forwarded to the Sponsor’s pharmacovigilance group, 
 
, via the study event form within 24 hours of becoming aware of any of the 
following events: 
• All SAEs, regardless of causality 
• Overdose (with or without an AE) 
• Inadvertent or accidental exposure 
• Pregnancy  
12.2.5.2. Timeframe for Collecting and Reporting Serious Adverse Events and Other 
Immediately Reportable Events 
SAEs and other events requiring expedited reporting occurring after administration of study drug 
and through 30 days after the last dose of study drug (or for discontinued subjects, within 30 
days after his/her last dose of study drug) must be reported to 
 within 
24 hours of the time any study staff member is made aware of the event. Event information 
should be emailed to 
 and to relevant study team 
members. Additional eCRF and/or paper documentation may need to be supplied to 
. 
12.2.5.3. Regulatory Notification  
US WorldMeds is responsible for notifying the relevant regulatory authorities of certain events. 
It is the Principal Investigator’s responsibility to notify the Institutional Review Board (IRB) or 
Independent Ethics Committee (IEC) of all SAEs that occur at his or her site. Investigators will 
also be notified of all unexpected, serious, drug-related events that occur outside of this study or 
at other sites in this study. Each site is responsible for notifying his or her IRB or IEC of these 
additional SAEs. 
12.2.6. 
Pregnancy 
Although pregnancy is not considered an AE, it is the responsibility of the Investigator 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 after the last dose of study 
drug to
. All subjects who become pregnant must be discontinued and must 
be followed until completion/termination of the pregnancy. If the pregnancy continues to term, 
the outcome (health of infant) and status of mother and child must also be reported to
 
. 


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13. 
STATISTICS 
13.1. 
General Statistical Considerations 
This section is an overview of the planned statistical analyses. Additional analyses and details 
will be provided in the statistical analysis plan, which will be finalized before database lock. 
Continuous or ordered categorical variables will be summarized with the mean, standard 
deviation, minimum, median, and maximum. Categorical variables will be summarized with 
counts and percentages. 
13.2. 
Sample Size Determination 
A sample size of 30 subjects per group provides adequate precision for the estimated treatment 
difference for the incidence of adverse withdrawal events during an opioid taper. Precision of the 
estimated difference is quantified by the width of the 95% confidence interval for the treatment 
difference. When the difference in proportions is 0.2, the 95% confidence interval is 0.2 ± 0.24 
when n=20/group and is 0.20 ± 0.17 when n=40/group (Figure 2). 
Figure 2: 
Width of 95% Confidence Interval as a Function of Sample Size 
 
0.68
0.48
0.39
0.34
0.3
0.28
0.26
0.24
0.230.21
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0
10
20
30
40
50
60
70
80
90
100
Subjects/Group
Width of 95% CI


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13.3. 
Analysis Populations 
Analysis populations are defined in Table 12. 
Table 12: 
Analysis Populations 
Analysis Population 
Description 
Safety 
All subjects who take at least 1 dose of study drug. Subjects will be 
analyzed according to the treatment they actually received. 
Intent-to-Treat 
All subjects in the Safety Population who have at least 1 
effectiveness assessment after Baseline. Subjects will be analyzed 
according to the treatment they are actually randomized to. 
13.4. 
Statistical Analyses  
13.4.1. 
Effectiveness Analyses 
13.4.1.1. Successful Completion of Opioid Taper 
The treatment group difference in the proportion of subjects who successfully complete the 
opioid taper will be summarized descriptively with a 95% confidence interval. The 95% 
confidence interval will be calculated based on the normal approximation for the binomial 
distribution, using the Wald continuity correction [(1/n1 + 1/n2)/2]. In addition, the treatment 
group difference will be tested with Cochran-Mantel-Haenszel (CMH) test stratified by total 
opioid dose (<90 MED, ≥90 MED) in ITT population. 
The percentage of subjects who meet each of the components of successful completion of opioid 
taper will be summarized. 
13.4.1.2. COWS, SOWS-Gossop, and SOWS-H 
The treatment group difference for change in COWS, SOWS-Gossop, and SOWS-H total scores 
from Baseline to peak value and to each scheduled evaluation will be summarized descriptively 
with 95% confidence intervals. The treatment group differences will be calculated within the 
framework of analysis of covariance (ANCOVA) with treatment and total opioid dose (<90 
MED, ≥90 MED) as fixed factors and baseline score as a covariate.  
13.4.1.3. MCGI-R and MCGI-S 
MCGI-R and MCGI-S will be summarized descriptively and analyzed by a CMH test stratified 
by total opioid dose (<90 MED, ≥90 MED) in ITT population.  
The frequency distribution across response scores will also be summarized. 
13.4.1.4. Time to Study Drug Discontinuation 
Time to study drug discontinuation will be summarized descriptively with a Kaplan-Meier curve 
stratified by total opioid dose (<90 MED, ≥90 MED) in ITT population. In addition, the 
treatment group difference will be assessed with the log-rank test.  


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13.4.1.5. Numerical Rating Scale 
Treatment group differences for each NRS score will be assessed as follows: 
• Average of daily values from Day 1 through EOS Visit 
• Change from Baseline (average of Days -3 to -1) to the average of the last 3 days 
before the EOS Visit 
• Graphical display of daily means 
Treatment differences for average of daily values and for change from baseline will be assessed 
with an ANCOVA with treatment and total opioid dose (<90 MED, ≥90 MED) as fixed factors 
and Baseline value (average of Days -3 to -1) as covariate. In addition, 95% confidence intervals 
for the treatment group differences will be calculated within the framework of the ANCOVA.  
13.4.1.6. ISI, HADS, EQ-5D-5L, and SF-36 
The treatment group difference for change in ISI, HADS, EQ-5D-5L, and SF-36 total scores and 
published subscale scores from Baseline to peak value and to each scheduled evaluation will be 
summarized descriptively with 95% confidence intervals. The 95% confidence intervals for the 
treatment group differences will be calculated within the framework of ANCOVA. The 
ANCOVA will have treatment and total opioid dose (<90 MED, ≥90 MED) as fixed factors and 
Baseline value as covariate. In addition, the treatment group difference will be tested within the 
ANCOVA framework. 
Scoring the SF-36 is a 2-step process.  
Step 1: Precoded numeric values are recoded per the scoring key given in Table 13. Note that 
all items are scored so that a high score defines a more favorable health state. In addition, 
each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 
and 100, respectively. Scores represent the percentage of total possible score achieved.  
Step 2: Items in the same scale are averaged together to create the 8 scale scores. Table 14 
lists the items averaged together to create each scale. Items that are left blank (missing data) 
are not taken into account when calculating the scale scores. Hence, scale scores represent 
the average for all items in the scale that the respondent answered. 


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Table 13: 
Recoding Items for the Short Form Health Survey 
Item Number 
Original Response Category 
Recoded Value 
1, 2, 20, 22, 34, 36 
1 
100 
 
2 
75 
 
3 
50 
 
4 
25 
 
5 
0 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 
0 
 
2 
50 
 
3 
100 
13, 14, 15, 16, 17, 18, 19 
1 
0 
 
2 
100 
21, 23, 26, 27, 30 
1 
100 
 
2 
80 
 
3 
60 
 
4 
40 
 
5 
20 
 
6 
0 
32, 33, 35 
1 
0 
 
2 
25 
 
3 
50 
 
4 
75 
 
5 
100 
Table 14: 
Definition of Average Scale Scores for Short Form Health Survey 
Scale 
Items Averaged for Scale Score 
Physical functioning 
3 4 5 6 7 8 9 10 11 12 
Role limitations due to physical health 
13 14 15 16 
Role limitations due to emotional problems 
17 18 19 
Energy/fatigue 
23 27 29 31 
Emotional well-being 
24 25 26 28 30 
Social functioning 
20 32 
Pain 
21 22 
General health 
1 33 34 35 36 


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13.4.1.7. Daily Dose of Opioids and Number of Non-Opioid Concomitant Medications for 
Withdrawal Symptoms 
The following endpoints will be summarized descriptively for each study day: 
• Change from Baseline to final, daily opioid dose, expressed as MED and as a 
percentage of this baseline MED 
• Number of non-opioid concomitant medications for withdrawal symptoms used by 
study day 
13.4.2. 
Safety Analysis 
All safety analyses will be performed on the Safety Population using the treatment actually 
received. All safety summaries will be descriptive; no statistical testing will be performed. 
13.4.2.1.1. Adverse Events 
A TEAE is defined as an AE with an onset that occurs after receiving study drug, or a continuing 
AE diagnosed prior to the date of first dose of study drug, which increases in severity after the 
start of dosing. AEs will be categorized by system organ class and preferred term with the 
Medical Dictionary for Regulatory Activities. 
Summary tables for TEAEs will include number and percent of subjects experiencing TEAEs by 
system organ class and preferred term. If a subject has more than 1 TEAE that codes to the same 
preferred term, the subject will be counted only once for that preferred term. Similarly, if a 
subject has more than 1 TEAE within a system organ class category, the subject will be counted 
only once in that system organ class category.  
The following TEAE summaries will be provided:  
• Overall summary of TEAEs  
• TEAEs by system organ class and preferred term  
• Drug-related TEAEs by system organ class and preferred term 
• TEAEs by system organ class, preferred term, and severity 
Serious TEAEs and TEAEs leading to study drug discontinuation will be identified. 
13.4.2.1.2. Clinical Laboratory Tests 
Change from Baseline will be summarized descriptively for each analyte. 
The percentage of subjects with treatment-emergent ALT, AST, or alkaline phosphatase 
>3 × ULN and total bilirubin >2.0 mg/dL at the same evaluation will be summarized by 
treatment group. 
Clinical laboratory results considered clinically important by the Investigator will be identified. 
Individual results for clinical laboratory tests (serum chemistry, hematology, and urinalysis) 
outside the normal range will be flagged in the data listings. Criteria to identify potentially 
clinically significant values will be defined in the Statistical Analysis plan. 


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13.4.2.1.3. Electrocardiogram 
The interpretation of electrocardiogram and interval duration measurements by the designated 
electrocardiogram laboratory cardiologists will be reviewed by the Investigator. Clinically 
significant deteriorations from Baseline will be reported and summarized as TEAEs. 
13.4.2.1.4. Vital Signs 
Change from Baseline to each scheduled measurement will be summarized descriptively. Criteria 
to identify potentially clinically significant values will be defined in the Statistical Analysis plan. 
13.5. 
Interim Analysis 
A Data Monitoring Committee (DMC) will be established to review safety and efficacy data in 
an unblinded manner. The DMC will consist of, at a minimum, 3 subject matter experts 
including a pain physician, psychiatrist/psychologist, and a statistician. A formal charter will be 
developed and signed prior to the unblinded interim analysis. The charter will address the review 
of safety data including AEs (eg, incidence of drop-outs due to AEs or intolerable opioid 
withdrawal, suicidality, cardiovascular events, urine drug screen results, alcohol test results, 
other laboratory results, etc) and stopping rules that will render the study unfeasible to continue 
(eg, a lack of measurable opioid withdrawal symptoms).  
The interim analysis will be conducted after approximately 30 subjects have completed or 
discontinued the study. There will be no formal statistical analysis for futility; however, the study 
may be stopped for futility, but it will not be stopped for a positive demonstration of 
effectiveness, providing the DMC determines the risk-benefit ratio is acceptable. Therefore, no 
adjustment of Type I error is necessary. 


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14. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
14.1. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Applicable International Council for Harmonisation (ICH) and Good Clinical Practice 
(GCP) guidelines  
• US Code of Federal Regulations (CFRs) dealing with Protection of Human Subjects 
(21 CFR Part 50), Financial Disclosure (21 CFR Part 54), IRBs (21 CFR Part 56) and 
Investigational New Drugs (21 CFR Part 312)  
• the Nuremberg Code 
• the Declaration of Helsinki, revised version of Seoul, October 2008 (in compliance 
with FDA guidance) 
• Applicable laws and regulations  
The purpose of these regulations, legal obligations, and guidelines is to define the standards and 
principles for the proper conduct of clinical trials that have been developed by the medical, 
scientific, and regulatory communities. They are not intended to impede or restrict clinical 
research. Copies of these materials can be downloaded from the FDA website at www.fda.gov. 
The protocol, protocol amendments, informed consent form (ICF), package insert for 
LUCEMYRA [USWM 2018], and any other relevant documents must be submitted to an 
IRB/IEC by the Investigator and reviewed and approved by the IRB/IEC before the study is 
initiated.  
The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
14.2. 
Informed Consent 
Properly executed informed consent, in compliance with 21 CFR 50, ICH guidelines, and 
regional/local regulations, shall be obtained from each subject before entering the subject into the 
study. Attention is directed to the basic elements that are required in the informed consent under 
US CFR for Protection of Human Subjects (21 CFR 50.25) and/or ICH E6 4.8.10. Where 
applicable, the consent form or appended document must also include required elements to 
maintain compliance with 45 CFR Part 164 (Heath Insurance Portability and Accountability Act) 
and/or 21 CFR Part 50.27/ICH E6 4.8.8.  


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Informed consent is a process of interaction between the Investigator and a potential subject in 
which the Investigator (or appropriate designee) explains the aims, methods, anticipated benefits 
(or lack thereof), and potential risks of participating in a study, and informs the potential subject 
of their rights. The subject will be given ample time and opportunity to inquire about details of 
the study so the subject can voluntarily make an informed decision about whether or not to 
participate in the study. All potential subjects will be given a current IRB- and Sponsor-approved 
copy of the ICF to read to ensure they are given accurate information, and to assist in verifying 
that consent was obtained. Information provided verbally, as supplemental explanation and/or 
answers to questions, must be accurate and consistent with the ICF, and must not be coercive or 
misleading. No subject will undergo any study procedures before the subject signs and dates the 
ICF, which should be signed before Screening. A completed, signed copy will be given to the 
subject and a signed original shall be maintained in the subject’s clinical file. Subjects who 
refuse to participate or who withdraw from the study will be treated without prejudice. 
Potential subjects are to be consented using an ICF that is written in a language they understand. 
If the person obtaining consent is not fluent in the language in which the consent is written (ie, is 
not able to explain the consent/answer questions to the subject), the subject’s consent must be 
witnessed by someone who is fluent in the language in which the consent is written, and must 
have the ability to translate any questions/explanations during the consent process. 
Each subject must also sign a Health Insurance Portability and Accountability Act authorization 
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. 
14.3. 
Source Documents and Retention 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Information recorded on source documents are to be attributable, legible, 
contemporaneous, original and accurate and allow reconstruction of the trial from start to finish. 
It is the responsibility of the Investigator to ensure that source documents capture all required 
information needed for the verification of data required by the protocol and that data captured on 
the eCRF match information recorded in source. The Investigator may need to request previous 
medical records from the subject’s primary care or other relevant physician. There may be 
instances where eCRF data are considered source data. These include the following assessments: 
• Subject completed questionnaires (electronic patient reported outcome) 
• Opioid Use Characterization 
• Characterization of Opioid Withdrawal History 
• Characterization of Pain Condition 
Source documents and site study records including signed informed consent forms are to be 
maintained on site during the duration of the study and retained by the Investigator for 2 years 
after study completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 


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14.4. 
Subject Confidentiality 
Subject confidentiality and privacy will be strictly held in trust by the participating Investigators, 
their staff, and the Sponsor(s) and authorized representatives of the Sponsor. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the Sponsor.  
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB, 
regulatory agencies or the pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the Investigator, including but not limited 
to, medical records (office, clinic, or hospital) and pharmacy records for the subjects in this 
study. The clinical study site will permit access to such records. 
Subjects will be assigned a unique identifier by the site. Any subject record or dataset that is 
transferred to the Sponsor or authorized representative of the Sponsor will contain the identifier 
only; subject names or any information which would make the subject identifiable will not be 
transferred.  
The study data entry and study management systems used by clinical sites and by research staff 
will be secured and password protected. At the end of the study, all study databases will be 
de-identified and archived. 
Subject confidentiality will be maintained in any publications or presentations that result from 
this study 
14.5. 
Study Monitoring and Data Quality 
The Sponsor or a clinical research organization will monitor the study. Study monitors perform 
source data verification to confirm that: 
• data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents 
• the safety and rights of subjects are being protected  
• the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements  
The Study Monitor serves as the investigative site’s primary contact. The Investigator should 
contact the Study Monitor if additional supplies are required, if there are changes to study 
personnel, or if the Investigator has questions regarding any aspects of the study. 
Study data monitoring may be conducted remotely by use of software that allows sites to scan, 
redact, and certify subject source records. The study monitoring plan will identify instances 
where an onsite visit is required, including monitoring report requirements. The purpose of 
monitoring is to verify that the clinical trial is being conducted and data are generated, recorded, 
and reported in compliance with the protocol, GCP, and applicable regulatory requirements. 
Findings of remote monitoring, or centralized review, may result in onsite visits, additional site 
training, corrective action plans, or site closure. The Data Coordinating Center will implement 
quality control procedures beginning with the data entry system (eCRF) and generate data 
quality control checks that will be run on the database. Any missing data or data anomalies will 


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be communicated to the site for clarification and resolution. In addition to data quality checks, 
centralized monitoring checks will be employed with the purpose of reviewing study 
performance metrics in addition to identifying trends of key data points within and across 
research centers. Findings of the centralized monitoring review may result in fewer or more 
onsite visits, additional site training, corrective action plans or site closure. The purpose of 
centralized monitoring is to ensure quality data throughout the study.  
14.6. 
Audits and Inspections 
The Investigator is required to make all study records promptly available for inspection, review, 
or audit at the study site upon request by the monitor, Sponsor, its representatives, or any 
appropriate regulatory agencies.  
The Sponsor may also request the Investigator to scan and email source documents with subject 
identifying information redacted to de-identify subject protected information. Additionally, as 
part of the informed consent process the Investigator should inform subjects about the potential 
of an audit by authorized representatives of the Sponsor and/or regulatory authorities and that 
confidentiality of the subject’s data will be maintained in accordance with local laws. 
14.7. 
Publication Policy 
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. 


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15. 
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Rauck, 2014 
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