Conditions: Opioid Dependence Acute Opioid Withdrawal Syndrome
Keywords: lofexidine opioid dependence acute withdrawal syndrome opioid withdrawal
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 603
Healthy volunteers: no

Brief summary:
The purpose of this study is to look at the efficacy and safety for lofexidine hydrochloride, an alpha-2 adrenergic agonist under development for the treatment of acute withdrawal from short-acting opioids. The study takes place in 2 parts: a 7-day inpatient double-blind treatment portion where subjects will be randomly assigned to one of three doses of study medication (2.4 mg total daily dose of lofexidine, 3.2 mg total daily dose of lofexidine, or placebo) followed by an optional open-label treatment period where subjects will be inpatient or outpatient and receive lofexidine at variable dosing for up to an additional 7 days. The Investigator hypothesizes that subjects will achieve maximum treatment effect with tolerable side effects at the 3.2 mg total daily dose and that both the 3.2 mg and 2.4 total daily doses will show better efficacy over placebo in treating symptoms of acute opioid withdrawal.

Detailed description:
This is a Phase 3, two-part, multicenter study to evaluate the dose-response, efficacy, and safety of lofexidine in alleviation of symptoms in subjects undergoing total and abrupt withdrawal from short-acting opioids. Any subject dependent on short-acting opioids (the primary projected indication for lofexidine) about to undergo opioid withdrawal will be eligible. Subjects will be evaluated for their compliance with protocol inclusion/exclusion criteria during a screening period, lasting up to 7 days.

The first part of the study will use an inpatient, randomized, double-blind, and placebo-controlled design (Days 1-7) followed by a second part, an open-label continuation treatment (Days 8-14). A total of 600 subjects will be randomized to receive lofexidine 2.4 mg total daily dose (0.6 mg QID), lofexidine 3.2 mg total daily dose (0.8 mg QID), or matching placebo in a 3:3:2 ratio (225:225:150) for 7 days (i.e., during the most intense stage of withdrawal). During the second part of the study (Days 8-14), all subjects, regardless of their treatment assignment (which will remain double-blinded), who successfully meet the definition for "completer" based on Days 1-7 (i.e., receives at least one dose of study medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop assessment on Day 7), will be eligible to receive open-label, variable dose lofexidine treatment (as determined by the Site Investigator, but not to exceed 3.2 mg/day) for up to an additional 7 days in either an inpatient or outpatient setting depending on the wishes of the investigator and the subject. No subject will receive lofexidine for more than 14 days total from the onset of abstinence. There will be no initial dose run-up and no mandated terminal dose taper.

Efficacy and safety assessments will be made daily throughout the study. Safety will be assessed by evaluation of adverse event, clinical labs, electrocardiograms (with special attention to QTc), vital signs, physical exam data, and the Columbia-Suicide Severity Rating Scale. Efficacy will be evaluated daily by subject- and observer-completed scales including the Short Opiate Withdrawal Scale of Gossop (SOWS-G)(the primary outcome measure is SOWS-G score area under the curve for Days 1-7), the Clinical Opiate Withdrawal Scales (COWS), Objective Opiate Withdrawal Scale (OOWS-Handelsman), the Visual Analog Scale for Efficacy (VAS-E), and the Modified Clinical Global Impressions scales for efficacy and side effects. Efficacy will also be evaluated by study retention, completion rates, concomitant medication use, incidence of withdrawal-related Adverse Events (AEs), and subject treatment status 30 days post last dose of study medication. Qualitative urine drug screening will be done every other day to monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use. Upon a subject's exit from the study, Study Discontinuation/End of Study assessments will be done.

During the study, study drug compliance will be documented in the source daily. During the first part of the study (Days 1-7), subjects will be inpatient and each dose of study medication will be administered by study site personnel and recorded in the source. Study medication will be dosed QID at 8 AM, 1 PM, 6 PM and 11 PM. During the second part of the study (Days 8-14), subjects who remain inpatient will be administered each dose of study medication by study site personnel and dosing will be captured in the source. Subjects who complete the second part of the study on an outpatient basis will return to the clinic daily for study assessments. During the open-label period, subjects will be dispensed 1-2 days worth of study drug, as needed to allow for flexibility in scheduling daily visits, to get them through until they are supposed to return the following day for additional study assessments and dosing.

Study medication will be held if vital signs meet any of the following criteria: Resting (sitting or recumbent, if required, for treatment of an adverse event): Systolic blood pressure \<90 mmHg and \>20% below screen value; Diastolic blood pressure \<50 mmHg and \>20% below screen value; Heart rate \<50 bpm and \>20% below screen value; and Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness, syncope).Orthostatic (after standing for 3 minutes): Systolic blood pressure diastolic blood pressure, or pulse \>25% below recumbent values.

A subject will be discontinued from the study if any of the following criteria are met: Systolic blood pressure \<70 mmHg and \>20% below screen value; Diastolic blood pressure \<40 mmHg and \>20% below screen value; Heart rate \<40 bpm and \>20% below screen value; QTc \>500 msec or \>25% above screen value for both males and females; Syncope; Subject misses more than 2 doses in 24 hours during Days 1-7 prior to meeting "completer" criteria (i.e., receives at least one dose of study medication on Day 7 and completed the 3.5-hour post-dose SOWS-Gossop assessments on Day 7); Subject misses a total of 6 doses during Days 1-7 prior to meeting "completer" criteria (i.e., receives at least one dose of study medication on Day 7 and completed the 3.5-hour post-dose SOWS-Gossop assessments on Day 7); Concomitant medication use (other than alumina, magnesia, and simethicone) for intolerable nausea and emesis.

Subjects should be discontinued from the study for any of the reasons listed below, and the event should be recorded as an Adverse Event (AE) and the subject followed until medically stabilized to the satisfaction of the attending physician: New onset of clinically significant abnormal ECG (e.g., second or third degree heart block or uncontrolled arrhythmia, prolonged QTcF interval); Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or fluids); Single occurrence of symptomatic bradycardia (as assessed by the Investigator, regardless of blood pressure) associated with chest pain, shortness of breath, or decreased level of consciousness; Persistent hypertension - blood pressure ≥185/110 mmHg recorded on 3 separate occasions taken at least 5 minutes apart AND within a 1-hour time period. If all 3 readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic ≥110 mmHg) the subject must be terminated; 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.

Arms:
arm 1: 225 subjects will be randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days. arm 2: 225 subjects will be randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days. arm 3: 150 subjects will be randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. arm 4: During the open-label portion of the study, subjects will be given the option to receive lofexidine HCl tablets for up to 7 days. Dosing regimens are at the discretion of the Investigator.

Interventions: intervention 1: Lofexidine HCl intervention 2: Placebo intervention 3: Open Label Lofexidine HCL
Intervention descriptions: intervention 1: Lofexidine HCl tablets will be available in 0.2 mg tablets. Lofexidine will be provided in total daily doses as indicated during the double blind portion of the study. intervention 2: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo. intervention 3: Lofexidine HCl tablets will are available in 0.2 mg tablets. During the optional open-label portion of the study, Lofexidine HCl can be prescribed at the discretion of the Investigator but total daily dose will not exceed 3.2 mg.

Protocol document:
ICF_002.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
SUBJECT INFORMATION AND CONSENT FORM AND 
AUTHORIZATION TO USE AND DISCLOSE PERSONAL HEALTH 
INFORMATION IN CLINICAL RESEARCH 
PROTOCOL NUMBER: USWM-LX1-3003-1 
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
TITLE: 
Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 
Efficacy, Safety, and Dose-Response Study of Lofexidine for Treatment 
of Opioid Withdrawal. Followed by Open-Label, Variable Dose 
Lofexidine Treatment.
DOCUMENT DATE: 25JUN2013 
NDA NUMBER: 209229 
NCT NUMBER: NCT01863186


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SUBJECT INFORMATION AND CONSENT FORM AND AUTHORIZATION TO USE AND 
DISCLOSE PERSONAL HEALTH INFORMATION IN CLINICAL RESEARCH 
 
 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, Safety, 
and Dose-Response Study of Lofexidine in the Treatment of Opioid Withdrawal (Days 1-
7) Followed by Open-Label, Variable Dose Lofexidine Treatment (Days 8-14) 
 
Sponsor: 
 
 
 
US WorldMeds, LLC 
 
 
 
 
 
 
 
Protocol Number:  
 
USWM-LX1-3003-1 
 
 
 
March 8, 2013 (inclusive of Amendment No. 1) 
 
 
 
Amendment No. 2 dated May 6, 2013 
 
 
 
 
Principal Investigator: 
 
 
 
 
 
 
 
Daytime telephone numbers: 
24-Hour Telephone: 
 
 
 
 
 
PURPOSE OF THE SUBJECT INFORMATION AND CONSENT FORM 
This Subject Information and Consent Form may contain words you do not understand.  Please ask the 
study doctor or the study staff to explain any words or procedures that you do not clearly understand. 
The purpose of this form is to give you information about the research study and, if signed, will 
give your permission to take part in the study.  The form describes the purpose, procedures, benefits, 
risks, discomforts, and precautions of the research study.  You should take part in this study only if 
you want to do so.  You may refuse to take part or withdraw from this study at any time without penalty 
or loss of benefits to which you are otherwise entitled.  Please read this Subject Information and 
Consent Form and ask as many questions as needed.  You should not sign this form if you have 
any questions that have not been answered to your satisfaction.  You will be asked to answer 
questions (Attachment #1) about the information contained in this Consent Form to demonstrate 
you understand it. 
PURPOSE AND DESCRIPTION OF THE RESEARCH STUDY 
You are being asked to take part in a research study of a drug called lofexidine to see if it is useful 
and safe in reducing opioid withdrawal symptoms in people who are addicted to opioids (for 
example, heroin and morphine).  Lofexidine is a non-addictive drug used in England to decrease 
symptoms of opioid withdrawal.  The Food and Drug Administration (FDA) has not yet approved 
lofexidine in the United States.  Because lofexidine is not FDA approved for treating opioid 
withdrawal, it is called an investigational drug.  In this study we are studying 2 dosage strengths of 
lofexidine, 2.4 mg and 3.2 mg, provided in tablet form for oral administration (by mouth). 


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You are being considered for participation in a 2-part research study because you are addicted to 
opioids and are seeking treatment for your addiction.  About 600 subjects at about 12 study sites 
across the United States will participate in this study.  It will take about 12 to 15 months to enroll 
600 subjects.   
If you participate in this study, you will be required to stay in a hospital, treatment facility or clinic 
for 7 days for the first part of the study where the study drug (lofexidine or placebo [contains no 
active drug]) will be provided in a randomized, double-blind manner.  This means that neither you, 
nor your study doctor, will know which treatment you are receiving (lofexidine 2.4 mg, lofexidine 
3.2 mg, or placebo).  The random assignment is like flipping a coin.  Based on the design of the 
study, 3 out of 4 (75%) subjects participating will receive active study drug (lofexidine) and 1 out of 
4 (25%) will receive placebo.  If medically necessary to know what study drug you have been given, 
the study doctor can request this information from the sponsor.  If you successfully complete the 
first part of the study, you will be eligible to receive active study drug treatment (lofexidine) for up to 
7 additional days during the second part of the study.  You will either remain in the hospital, 
treatment facility, or clinic for treatment with lofexidine or be discharged and treated with lofexidine 
as an outpatient, depending on the wishes of you and your study doctor.  The study will take place 
over a maximum of 21 days and the total number of days you may receive lofexidine is 14 days (up 
to 7 days in the first part of the study and up to 7 days in the second part of the study). 
STUDY PROCEDURES 
Screening 
If you agree to take part in this study, you will first review the consent form and HIPAA (Health 
Insurance Portability and Accountability Act) document with study staff.  You will need to pass the study 
consent quiz with 100% accuracy (if necessary, you can take the quiz more than once; Attachment 1).  
You must sign the consent and HIPAA forms before any study-related procedures can be performed, as 
described below.  Screening procedures and/or assessments may require up to 3 clinic visits and the 
information collected is used to determine if you are eligible to enter the study.  If you are not eligible, 
you will be assisted in finding other substance abuse treatment programs in your geographic area, if 
you so desire, at your own cost or through your regular health care provider. 
• 
Study staff will ask you a series of questions to check your eligibility to participate against a 
list of inclusion and exclusion criteria provided by the sponsor. 
• 
Study staff will collect your medical, smoking, and alcohol history and demographic information. 
• 
Study staff will collect your prior medication history (over last 30 days).  It is important to tell 
the study staff all of the medications you are taking, including prescription, nonprescription 
(over-the-counter medications), and herbal preparations. 
• 
A study doctor or designee will complete the Mini International Neuropsychiatric Interview 
(M.I.N.I.) questionnaire to document your addiction to opioids. 
• 
A study doctor or designee will complete the Objective Opiate Withdrawal Scale of 
Handelsman (OOWS-Handelsman) questionnaire to document the severity of your 
withdrawal symptoms. 
• 
A study doctor or designee will complete the Clinical Opiate Withdrawal Scale (COWS) 
questionnaire to document the severity of 11 common opioid withdrawal signs and 
symptoms. 
• 
A study doctor or designee will perform a complete physical examination and measure your 
blood pressure and pulse (while sitting or laying down and standing), respiration rate 
(breaths per minute) and temperature. Your height and weight will be collected also. 


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• 
You will have a blood sample drawn (about ½ ounce or 3 teaspoonfuls).  This blood will 
show the study doctor how various systems in your body, for example your liver and 
kidneys, are working.  Some people who have abused opioids for a long time do not have 
"good veins" even for a single blood draw.  If blood cannot be obtained for the required 
medical tests, you will not be eligible for participation in this study.   
• 
You will be assisted in finding other substance abuse treatment programs in your 
geographic area, if you so desire, at your own cost or through your regular health care 
provider. 
• 
You will have to provide an observed urine sample.  Some of this urine will be tested for 
drugs (like heroin and methadone), some will be used to see how your kidneys and other 
parts of your body are working, and some used for pregnancy testing as described 
immediately below. 
• 
If you are female and capable of becoming pregnant, some of the urine collected will be 
used for pregnancy testing.  The result must be negative to participate in the study.  If you 
are able to become pregnant, you must agree to using birth control for the entire duration of 
this research study.  Your study doctor will discuss acceptable forms of birth control. 
• 
You will be tested for infectious diseases (hepatitis, syphilis, and tuberculosis) and given the 
results of these tests.  If your tuberculosis skin test is positive, you will have a chest x-ray 
performed to assess active tuberculosis.  You will also have a chest x-ray performed if you have 
previously been positive for tuberculosis.  You will not be eligible for study participation if your 
syphilis or tuberculosis tests are positive, and you will be referred, at your own cost, for 
appropriate follow-up and/or treatment. You may still be eligible for study participation if you 
have a positive result for hepatitis but no active liver disease otherwise.  The study doctor 
should know if you have been exposed to a hepatitis virus in the past.  A positive result from 
these tests will be reported to the local health department as required by state law.  The results 
from these tests are confidential and results will not be shared outside of this study except as 
required by state law.  While expected to be confidential, these results, if disclosed, may affect 
your employment or health insurance options. 
• 
You will have an electrocardiogram (ECG) performed to measure the electrical activity of 
your heart.  This will be done 3 times (1 PM, 4 PM, and 5 PM) on one day during the 
screening period. 
Inpatient Treatment (Days 1-7) 
For the inpatient part of this study, you will be required to stay in a unit (hospital, treatment facility or 
clinic), which may or may not be locked, with or without visitors, and you will be required to follow all 
rules and regulations of the unit.  You will be allowed to eat only the food served at the unit (no 
carry-out).  If you are eligible to participate, you will be admitted in time to have the following 
assessments completed before you receive your first dose of study drug at 8 AM: 
• 
A study doctor or designee will complete the OOWS-Handelsman to document the severity of 
your withdrawal symptoms. 
• 
A study doctor or designee will complete the COWS questionnaire to document the severity of 
11 common opioid withdrawal signs and symptoms. 
• 
You will complete the Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) questionnaire 
to document the severity of your withdrawal symptoms. 
• 
A study doctor or designee will complete the Columbia-Suicide Severity Rating Scale(C-SSRS) 
(baseline version) to document any suicidal thoughts or behaviors over your lifetime. 
• 
A study doctor or designee will perform a physical exam to see if you have any new medical 
problems since your screening visit. 


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• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down and standing), respiration rate (breaths per minute) and temperature. 
• 
You will have a urine drug screen performed. 
• 
If you are a female capable of becoming pregnant, you will have a urine pregnancy test 
performed. 
• 
Study staff will ask about any medications you have taken since your screening visit. 
Study drug (lofexidine or placebo) will start after the above procedures confirm you are eligible to 
participate in this study.  You will be given 4 tablets of study drug 4 times a day (8 AM, 1 PM, 6 PM, 
and 11 PM) for 7 days.  If your random assignment is to lofexidine 2.4 mg, you will receive 3 x 
0.2 mg tablets plus 1 placebo tablet (no active drug).  If your random assignment is to lofexidine 
3.2 mg, you will receive 4 x 0.2 mg lofexidine tablets.  If your random assignment is to placebo, you 
will receive 4 placebo tablets (no active drug).  In all, you will receive 16 tablets each day while in 
the unit.  The tablets will appear identical so neither you nor the study doctor or staff knows which 
treatment you are receiving. 
Medicines other than those your doctor gives you are not permitted.  Allowed medicines your doctor 
may give you include multivitamins, nicotine replacement therapy (patch, inhaler, gum, nasal 
spray), and other medications to treat minor complaints such as diarrhea; constipation; indigestion 
and nausea; headache, muscle aches, and other discomforts; cough; and insomnia.  If you are 
admitted to the unit the day before the study starts, you may be administered a single dose of an 
opioid (for example, morphine) to keep you reasonably comfortable. 
You may be allowed to smoke in the unit, if smoking is permitted in the unit.  If you usually smoke 
tobacco products, the doctors will offer and encourage you to use nicotine replacement medications 
(for example, nicotine patch, gum, inhaler, or nasal spray) while you are in the unit to treat your 
nicotine withdrawal symptoms and to make it easier for you not to smoke.  If smoking is allowed, 
smoking breaks outside the inpatient locked unit will be constantly observed and supervised. 
The following assessments will be completed every day (unless otherwise specified) while you are 
in the unit on Days 1-7: 
• 
A study doctor or designee will complete the OOWS-Handelsman questionnaire each day 
(3.5 hours after the first dose) to document the severity of your withdrawal symptoms. 
• 
A study doctor or designee will complete the COWS questionnaire each day (3.5 hours after the 
first dose) to document the severity of 11 common opioid withdrawal signs and symptoms. 
• 
A study doctor or designee will complete the Modified Clinical Global Impression (MCGI) 
questionnaire each day (3.5 hours after the first dose) to document your overall benefit of 
treatment with study drug.  You will also complete this questionnaire (separate from the study 
doctor/designee). 
• 
A study doctor or designee will assess whether you have completed detoxification (i.e., removal 
of the opioid(s) from your body) after completion of dosing for this part of the study but before 
beginning dosing for the second part of the study. 
• 
You will complete the SOWS-Gossop questionnaire each day (3.5 hours after the first dose) to 
document the severity of your withdrawal symptoms. 
• 
You will complete the visual analog scale (VAS) for efficacy (VAS-efficacy) questionnaire each 
day (3.5 hours after the first dose) to document how much the study drug is helping your 
withdrawal symptoms. 
• 
A study doctor or designee will complete the C-SSRS (since last visit version) each day 
(3.5 hours after the first dose) to document any suicidal thoughts or behaviors since the last 
time the scale was completed.  


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• 
Study staff will document any medications you have taken. 
• 
Study staff will monitor you continuously for side effects. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down and standing), respiration rate and temperature before every dose and 3.5 hours after the 
8 AM, 1 PM, and 6 PM doses. 
• 
A study doctor or designee will perform a complete physical exam 3 to 4 hours after 
randomization on Day 1 and after completion of dosing for this part of the study but before 
beginning dosing for the second part of the study. 
• 
You will have an ECG performed 10 times:  on Days 1 and 7 (before the first daily dose, before 
the 1 PM dose, at 4 PM, and at 5 PM) and on Days 2 and 4 (before the first daily dose). 
• 
You will have a finger prick blood sample collected at the same time the ECGs are performed, 
and on Days 3 and 6 at 9 PM and 10 PM 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected after 
completion of dosing for this part of the study but before beginning dosing for the second part of 
the study, and more often if clinically needed to monitor your health. 
• 
You will have a urine drug screen performed at least every other day. 
Inpatient or Outpatient Treatment (Days 8-14) 
If you successfully complete the first 7 days of inpatient treatment (that is, you receive at least one 
dose of study medication on Day 7 and complete the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7), you may be eligible to receive active study drug treatment (lofexidine) for 
up to 7 additional days during the second part of the study (Days 8-14).  Your study doctor will 
decide if lofexidine is needed for you and, if so, you will either remain in the unit for treatment 
with lofexidine or be discharged and treated with lofexidine as an outpatient.  Your study doctor 
will also decide what dose(s) of lofexidine you will receive during this part of the study, but the 
dose will not be higher than 3.2 mg per day.  Lofexidine treatment will be stopped and you will 
be discontinued from the study at any time during Days 8-14 if your study doctor decides that 
you no longer need treatment with lofexidine to control your withdrawal symptoms. 
The assessments listed below will be performed every day (unless otherwise specified) on    
Days 8-14.  If you are an outpatient, you will be required to return to the study site every day to 
have these assessments completed. 
• 
A study doctor or designee will complete the OOWS-Handelsman questionnaire to document 
the severity of your withdrawal symptoms. 
• 
A study doctor or designee will complete the COWS questionnaire to document the severity of 
11 common opioid withdrawal signs and symptoms. 
• 
A study doctor or designee will complete the MCGI questionnaire to document your overall 
benefit of treatment with study drug.  You will also complete this questionnaire (separate from 
the study doctor/designee). 
• 
A study doctor or designee will assess whether you have completed detoxification. 
• 
You will complete the SOWS-Gossop questionnaire to document the severity of your withdrawal 
symptoms. 
• 
You will complete VAS-efficacy questionnaire to document how much the study drug is helping 
your withdrawal symptoms. 
• 
A study doctor or designee will complete the C-SSRS (since last visit version) to document any 
suicidal thoughts or behaviors since the last time the scale was completed. 


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• 
Study staff will document any medications you have taken. 
• 
Study staff will monitor you continuously for side effects, if inpatient.  If outpatient, study staff will 
ask you about any side effects you may have experienced since your last visit. 
• 
A study doctor or designee will measure your blood pressure and pulse (while sitting or laying 
down and standing) at least once daily before dosing and 3.5 hours after dosing on Days 8-13 
and on Day 14 before a dose.  If you are being treated on an outpatient basis during Days 8-13 
and cannot stay in the clinic for the 3.5-hour measurements, you will be given a portable blood 
pressure machine to measure your blood pressure and pulse and a paper diary to record the 
values. 
• 
You will have an ECG performed 3 times:  on Day 8 before the first daily dose and 3.5 hours 
after first daily dose and on Day 14 before a dose. 
• 
A study doctor or designee will perform a complete physical exam as needed to monitor your 
health. 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples as needed to monitor 
your health. 
• 
You will have a urine drug screen performed at least every other day. 
• 
If you are being treated as an outpatient, you will need to return the dispensed study medication 
bottles every day when you return to the clinic so the study staff can account for all study 
medication. 
Study Discontinuation/End of Study  
When you complete or if you are removed from the study for any reason, you will have the following 
assessments completed after your last dose of study medication: 
• 
A study doctor or designee will complete the OOWS-Handelsman, COWS, MCGI and C-SSRS 
questionnaires. 
• 
A study doctor or designee will assess whether you have completed detoxification. 
• 
You will complete the SOWS-Gossop, MCGI, and VAS-efficacy questionnaires. 
• 
Study staff will ask about any medications you have taken and any side effects you may 
have experienced since your last visit. 
• 
You will have an ECG performed. 
• 
A study doctor or designee will perform a complete physical examination and measure your 
blood pressure and pulse (while sitting or laying down and standing), respiration rate, 
temperature, and weight. 
• 
You will have blood (about ½ ounce or 3 teaspoonfuls) and urine samples collected to 
document your overall health. 
• 
If you are a female of childbearing potential (capable of being pregnant), you will have a 
urine pregnancy test. 
• 
You will have a urine drug screen performed. 
• 
If you are being treated as an outpatient, you will need to return the dispensed study 
medication bottle when you return to the clinic so the study staff can account for all study 
medication. 
Study staff will contact you by telephone 30 days after your last dose of study medication to ask you 
about your current treatment status (for example, current psychosocial treatment, relapse, or 


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successful entry into another substance abuse treatment program) and any side effects you may 
have experienced since your last visit. 
SUBJECT OBLIGATIONS 
If you are a female and capable of becoming pregnant, you must use birth control during your 
participation in the study.  You can discuss birth control options with your study doctor. 
You will be allowed to take some medications during the study including multivitamins, nicotine 
replacement therapy (patch, inhaler, gum, nasal spray), and medications to treat minor complaints such 
as diarrhea (Pepto-Bismol); constipation (dioctyl sodium sulfosuccinate and psyllium hydrocolloid 
suspension); indigestion and nausea (Alumina, Magnesia, and Simethicone); headache, muscle aches, 
and other discomforts (Tylenol); cough (guaifenesin); and insomnia (Zolpidem).  It is very important 
that you discuss with the study doctor before you begin taking any other prescription or 
nonprescription (over-the-counter) medications, or herbal preparations to make sure they are 
acceptable to take with the study drug.  Some drugs may have dangerous interactions with lofexidine, 
as described further in the section immediately below. 
RISKS OR DISCOMFORTS 
Lofexidine, as an investigational drug, may involve some risks to you that are currently unknown.  
Your opioid withdrawal symptoms may improve, not change, or may worsen if you take part in this 
research study. 
There is a chance that you may experience opioid withdrawal symptoms during the study including 
nausea, vomiting, diarrhea, muscle pain, abdominal discomfort, sweating, runny nose, watery eyes, 
restlessness, tremors, chills, increased heart rate and blood pressure, and agitation. 
You may experience some side effects from the study drug.  Lofexidine, at the doses planned in this 
study, may cause a decrease in blood pressure and pulse and cause dizziness, especially when you 
stand up too quickly.  After the study drug is discontinued, you may experience a temporary increase 
in blood pressure.   
You may also experience drowsiness and/or dry mouth, nose, or throat while taking lofexidine.  Other 
rare side effects of lofexidine that have been reported by less than 5% of subjects in other completed 
trials, which are listed in the Investigator's Brochure for lofexidine, may include trouble breathing, very 
slow heart rate, severe skin rash, faintness, unusual tiredness or extreme weakness, constipation, or 
loss of appetite.  There are also some reports of the QTc interval of the heart being too long in people 
taking lofexdine.  The QTc interval is a measurement on an ECG reading that shows the electrical 
activity in the heart’s lower chambers, the ventricles.  When the careful timing of the heart’s patterns 
are upset or disrupted and the QTc interval is longer than usual; it can lead to fainting, heart attack, or 
sudden death.  There was one report of a person who experienced Torsades de Points, a potentially 
fatal abnormal heart rhythm (although this patient recovered).  Torsades de Pointes is an irregular 
heartbeat caused by the heart’s lower chambers beating faster than usual, causing less blood to 
pump out of the heart, which leads to sudden fainting.  If the episode is short, the heart can correct 
itself on its own.  If an episode of Torsades de Points persists, however, it can lead to an irregular 
heartbeat known as ventricular fibrillation (a condition causing the lower chambers of the heart to beat 
so fast that the heart shakes and stops pumping blood) and possibly death. 
You should be aware that you will probably be more sensitive to the effects of heroin and other 
opioids after you complete this study.  You should be extremely careful after you leave the study, if 
you decide to use opioids again.  Any opioid, even at doses you took in the past, could cause an 
overdose, severe medical problems, or even death. 


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Consent Date:  June 25, 2013 
 
Page 8 of 14 
Risks associated with drawing blood from your arm or by finger stick include pain, bruising, 
lightheadedness and, on rare occasions, infection.  Precautions will be taken to minimize these risks.  
The total amount of blood that you will be asked to give during the study is about 1.5 ounces             
(9 teaspoonfuls).  This is much less than a unit of blood (about 16 ounces) typically given during a 
blood donation. 
Some drugs may have dangerous interactions with lofexidine and should not be used together.  Using 
lofexidine and beta-receptor blockers (to treat high blood pressure) together may cause a very low 
heart rate.  Using lofexidine with alcohol, sedatives, and/or antihistamines may enhance central 
nervous system depressant effects (for example excessive sleepiness).  Before starting any new 
medications, you should talk with your study doctor. 
Nicotine Replacement Medications:  You should not smoke if you are being treated with nicotine 
replacement medications since this may result in high levels of nicotine in your blood.  Signs and 
symptoms of high levels of nicotine in your blood are nausea, vomiting, abdominal pain, diarrhea, 
weakness, dizziness, loss of color, cold sweats, tremor, mental confusion, headache, and disturbed 
hearing and vision. 
In addition to the risks or discomforts listed above, there may be other risks that are currently not 
known.  Also the risks or discomforts described may occur more often or be more severe than has 
been seen before. 
REPRODUCTIVE RISKS 
The effects of lofexidine on the human fetus are unknown.  High doses of lofexidine given to 
pregnant mice, rats, and rabbits caused a reduction in fetal weights and slight increase in fetal 
resorptions (loss of fetus with the fetus absorbed within the pregnant animal's body).  If you 
become pregnant while in this research study, an injury to the fetus may occur that has not been 
seen before.  Additionally, the effects on an infant, through breast feeding (nursing), are unknown. 
If you become pregnant during the study or within 30 days after study completion, notify your study 
doctor immediately.  Your pregnancy will be followed to outcome. 
NEW FINDINGS 
Your study doctor will tell you of any information learned during the course of the study that might cause 
you to change your mind about taking part in this research study.  You may contact the study doctor at 
any time after your participation ends to find out if any new information about this study has become 
available. 
POSSIBLE BENEFITS 
Your opioid withdrawal symptoms may be reduced while participating in this study but we cannot 
guarantee that you will receive any benefits by taking part in this study.  Your participation in the study 
will contribute to information about this non-addictive study drug and may benefit other patients 
addicted to opioids in the future. 


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Protocol Number: USWM-LX1-3003-1 
 
Subject Initials: ________ 
 
Consent Date:  June 25, 2013 
 
Page 9 of 14 
PAYMENT TO SUBJECT FOR PARTICIPATION 
For your participation, you will be paid for your time and inconvenience as follows: 
Screening (up to 3 visits): 
 
Days 1-7 (Inpatient): 
 
 
 
 
 
 
Days 8-14 (Inpatient/Outpatient): 
 
The maximum compensation you may receive for your participation in this research study is 
 in 
the event you require 3 screening visits and you participate through Day 14. 
If you require transportation for clinic visits, you may be reimbursed for expenses (after you submit 
receipts) or transportation may be provided by the study site. 
You will receive compensation by cash, check, or vouchers in accordance with your local study site’s 
policies. 
COSTS 
You do not have to pay for your stay in the unit, study visits, and for any treatment or testing done as 
part of this research study. 
ALTERNATIVE TREATMENTS 
No non-opioid drugs are currently approved by the U.S. FDA for the treatment of opioid withdrawal 
signs and symptoms.  You do not have to take part in this research study, however, to receive 
treatment for your condition.  If you decide not to take part in this study, a study doctor will discuss 
alternative treatments with you.  Two prescription drugs (buprenorphine and methadone) are available 
to treat your withdrawal symptoms.  Both of these drugs are opioids and have side effects and risks 
associated with their use.  Individual and/or group counseling may also help your condition.  The study 
researchers will, at your request, refer you to public or private substance abuse treatment programs in 
your geographic area, at your own cost or through your regular health care provider.  Refusal to 
participate in this study will not affect other medical care for which you may be eligible. 
CONFIDENTIALITY AND RELEASE OF MEDICAL RECORDS 
We will protect information about you and your taking part in this research study to the best of our ability.  
To help protect your privacy, the study sponsor (US WorldMeds) has obtained a Certificate of 
Confidentiality from the National Institutes of Health (NIH).  With this certificate, the researchers cannot be 
forced to disclose information that may identify you, even by a court subpoena, in any federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. 
The Certificate of Confidentiality does not prevent the researchers, however, from disclosing voluntarily, 
without your consent, information that would identify you as a participant in the research study under 
certain circumstances (for example, abuse, neglect, harm to self, harm to others, and certain cases of 
communicable diseases).  In addition, absolute confidentiality cannot be guaranteed because medical 
records and study information that identify you may need to be audited or evaluated by authorized staff 
from the U.S. FDA, Institutional Review Board (IRB), the study sponsor (US WorldMeds), and other 
health authorities to meet their specific requirements.   
These agencies and researchers are bound by rules of confidentiality, however, and they make every 
effort not to release information that identifies you.  If information about this study is published, your 
name, initials, or any other identifying information will not be given. 


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Protocol Number: USWM-LX1-3003-1 
 
Subject Initials: ________ 
 
Consent Date:  June 25, 2013 
 
Page 10 of 14 
Data collected during the study (including laboratory specimens, medical records, and other data forms 
and records) will be stored in a way that does not identify you by name.  Research and clinical records 
will be stored in a locked cabinet.  Only selected study researchers will have access to this information 
and they are bound by rules of confidentiality not to reveal identifying information to others. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
RESEARCH RELATED INJURY 
If you are injured as a result of the study drug or study procedures performed during your inpatient 
participation in this research study, you will receive medical care at the study site or an emergency 
department as clinically necessary.   
If you are injured as a result of the study drug or study procedures performed during your outpatient 
participation in this research study, you should seek medical attention at the health care provider of 
your choice or an emergency department if necessary.  The sponsor or study site will cover the 
medical expenses necessary to treat the injury only to the extent that such costs are not covered by your 
health insurance policy, by a government program, or by any other third party. 
You must follow the directions of the study doctor to be eligible for this coverage. 
Neither the sponsor nor the study doctor/study site has a program in place to provide other 
compensation in the event of an injury. 
LEGAL RIGHTS 
You do not waive any legal rights by signing this Subject Information and Consent Form. 
VOLUNTARY PARTICIPATION 
Your decision to take part in this research study is completely voluntary.  There will not be any penalty 
or loss of benefits to you if you decide not to take part.  You will be informed of any significant new 
information that becomes available during the course of the study that might affect your decision to 
continue your participation in the study. 
You may drop out of this study at any time.  Because there may be risks associated with this decision, 
you should inform the study staff.  They will assist you in properly ending your participation, 
including returning to the clinic for tests if you are an outpatient.   


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Protocol Number: USWM-LX1-3003-1 
 
Subject Initials: ________ 
 
Consent Date:  June 25, 2013 
 
Page 11 of 14 
If you leave the study early, you will be assisted in finding other substance abuse treatment 
programs in your geographic area, if you so desire, at your own cost or through your regular 
health care provider. 
WITHDRAWAL 
Your doctor, the sponsor company, or the FDA has the right to stop your participation in the study at any 
time, with or without your consent, for any of the following reasons: if you have an adverse effect from 
the study drug, if you have an adverse effect from the study drug; if you need a treatment not allowed 
in this study; if you fail to follow the study procedures; if you become pregnant; or if the study is 
canceled by the FDA or the sponsor company.  The sponsor may decide to stop the study and 
your access to the study under certain circumstances, even if the study drug appears to be safe and 
effective.  You may drop out of this research study at any time, without penalty (see above). 
CONTACT FOR QUESTIONS 
If you have any questions about your participation in this research study, or if you feel that you 
have experienced a research-related injury or reaction to the study drug, contact the study 
doctor at the telephone number listed on page 1 of this form. 
This study was reviewed by 
  An IRB reviews research to 
protect the rights and welfare of study participants.  If you have problems, concerns, suggestions, 
questions or information about the study, and for information regarding research subject's rights, 
please call 
 
(toll free). 
Although 
has approved the information provided in this informed consent form and has 
granted approval for the investigator to conduct the study this does not mean 
 has approved 
your participation in the study.  You must evaluate the information in this informed consent form for 
yourself and decide whether or not you wish to participate. 
AUTHORIZATION TO USE AND DISCLOSE PERSONAL HEALTH INFORMATION FOR 
RESEARCH 
The United States government has issued a new privacy rule to protect the privacy rights of patients.  
This rule was issued under a law called the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  The Privacy Rule is designed to protect the confidentiality of your personal health 
information.  The document you are reading, called an “Authorization,” describes your rights and 
explains how your health information will be used and disclosed (shared). 
In working with the sponsor, the study doctors will use and share personal health information about 
you.  This is information about your health that also includes your name, address, telephone number, 
or other facts that could identify the health information as yours.  This includes information in your 
medical record and information created or collected during the study.  This information may include 
results of your medical history, physical exam, and laboratory tests (blood, urine, and ECG).  Some of 
these tests may have been done as part of your regular care.  The study doctor will use this 
information about you to complete this research. 
In most cases, the study doctor will use your initials and assign a code number to your information 
that is shared with the sponsor.  The sponsor and its representatives may review or copy your 
personal health information at the study site.  Regulatory authorities and the IRB may also review or 
copy your information to make sure that the study is done properly or for other purposes required by 
law. 


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Protocol Number: USWM-LX1-3003-1 
 
Subject Initials: ________ 
 
Consent Date:  June 25, 2013 
 
Page 12 of 14 
By signing this Authorization, you allow the study doctor to use your personal health information to 
carry out and evaluate this study.  You also allow the study doctor to share your personal health 
information with: 
• 
the sponsor and its representatives; 
• 
 
• 
the U.S. FDA; and 
• 
other regulatory agencies. 
Your personal health information may be further shared by the groups above.  If shared by them, 
the information will no longer be covered by the Privacy Rule.  These groups, however, are committed 
to keeping your personal health confidential. 
You have the right to see and get a copy of your records related to the study for as long as the study 
doctor has this information.  By signing this Authorization, however, you agree that you might not be able 
to review or receive some of your records related to the study until after the study has been completed. 
You may choose to withdraw this Authorization at any time, but you must notify the study doctor in 
writing.  Give your written withdrawal notice to your study doctor if you are being treated as an 
inpatient.  If you are being treated as an outpatient, send your written withdrawal notice to the study 
doctor at the address listed on page 1 of this form. 
If you withdraw from the study and withdraw your Authorization, no new information will be collected for 
study purposes unless the information concerns an adverse event (a bad effect) related to the study.  If 
an adverse event occurs, your entire medical record may be reviewed.  All information that has already 
been collected for study purposes, and any new information about an adverse event related to the study, 
will be sent to the study sponsor. 
If you withdraw from the study but do not withdraw your Authorization, new personal health information may 
be collected until this study ends. 
This authorization does not have an expiration date.  If you do not withdraw this Authorization in writing, it 
will remain in effect indefinitely.  Your study doctor will keep this Authorization for at least 6 years. 
If you do not sign this Authorization, you cannot participate in this research study or receive study-related 
treatment.  If you withdraw this Authorization in the future, you will no longer be able to participate in this 
study.  Your decision to withdraw your Authorization or not to participate will not involve any penalty or 
loss of access to treatment or other benefits to which you are entitled. 


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Protocol Number: USWM-LX1-3003-1 
 
Subject Initials: ________ 
 
Consent Date:  June 25, 2013 
 
Page 13 of 14 
 
VOLUNTEER'S STATEMENT: 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, Safety, and  
Dose-Response Study of Lofexidine in the Treatment of Opioid Withdrawal (Days 1-7)  
Followed by Open-Label, Variable Dose Lofexidine Treatment (Days 8-14) 
 
 
I have been given a chance to ask questions about this research study.  These questions have been 
answered to my satisfaction.  I may contact the study doctor if I have any more questions about taking 
part in this study.  The study doctor or the company he/she is employed by is being paid by the 
sponsor for my participation in this study. 
I understand that my participation in this research project is voluntary.  I know that I may quit the study 
at any time without harming my future medical care or losing any benefits to which I might be 
entitled.  I also understand that the investigator in charge of this study may decide at any time that 
I should no longer participate in this study. 
If I have any questions about my rights as a research subject in this study I may contact 
 at 
(toll free). 
By signing this form, I have not waived any of my legal rights. 
I have read and understand the above information.  I agree to participate in this study.  I understand 
that I will be given a copy of this signed and dated form for my own records. 
 
 
__________________________________  
 
_______________ 
Study Participant (signature) 
  
 
 
Date 
 
__________________________________ 
Print Participant’s Name 
 
 
__________________________________  
 
_______________ 
Person who explained this study (signature)  
 
Date 
 
 

Prot_001.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
PROTOCOL NUMBER / AMENDMENT: USWM- LX1-3003-1 / 02 
 
  
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
 
 
TITLE: 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety, and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine 
Treatment (Days 8-14) 
 
 
DOCUMENT DATE: 06MAY2013 
NDA NUMBER: 209229 
NCT NUMBER: NCT01863186 


US WorldMeds, LLC 
Clinical Study Report – USWM-LX1-3003-1 
 
 
 
 
16.1 
STUDY INFORMATION 
16.1.1 
PROTOCOL AND AMENDMENTS 
 
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Confidential Information
Page 1 of 80
CLINICAL STUDY PROTOCOL
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety, and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine
Treatment (Days 8-14)
Protocol Number:
USWM-LX1-3003-1
Product:
Lofexidine
Investigational New Drug (IND) Number:
IND 47,857
Development Phase of Study:
Phase 3
Medical Monitor:
Contract Research Organization (CRO):
Sponsor:
US WorldMeds, LLC
4010 Dupont Circle, Ste L-07
Louisville, KY  40207
Protocol Date:
August 10, 2012
Amendment No. 01 Date:
March 8, 2013
Amendment No. 02 Date:
May 6, 2013
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.
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Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 2 of 80
1 PROTOCOL AMENDMENT SUMMARY
Changes made in this amendment to the protocol for Study USWM-LX1-3003-1
(Amendment No. 02) are listed below along with the rationale to support these changes.
Location
Modification/Rationale
Synopsis; 11.2.2
Exclusion criterion #3: For clarity, the footnote regarding infectious 
disease panel was removed from footnotes and the sentence inserted 
into the text.
Exclusion criterion #5 was modified to not only exclude subjects 
with self-reported AIDS but also subjects who are HIV positive and 
taking retroviral medications.
Synopsis; Table 1; 
13.2.1; 13.2.2; 
15.2; 15.3.1; 
15.3.2; 15.3.3; 
15.5.2
Text was clarified to indicate that vital signs will be recorded at rest 
(i.e., sitting or recumbent, if required, for treatment of an adverse 
event) and standing. Respiration and temperature were added as 
items to be measured along with blood pressure and pulse while at 
rest (i.e., respiration and temperature are not required measurements 
after standing) during Days 1-7. Also the requirement for the 
3.5-hour post-dose measurement on Day 14 was removed, as was 
the requirement that pre-dose vital signs be measured before the 
“first daily dose.” Now Day 14 measurements can be obtained 
before any dose that day.
Synopsis; Table 1; 
15.3.2; 15.5.3
The requirement for the 3.5-hour post-dose ECGs on Day 14 was 
removed, as was the requirement that the pre-dose ECG be 
measured at the “first daily dose.”  Now the Day 14 ECG can be 
obtained before any dose that day.
Synopsis; Table 1;
15.3.2; 15.5.4.1; 
15.5.4.4; 15.5.5
The requirement for clinical laboratory testing, pregnancy testing, 
and a complete physical exam on Day 14 was removed.  Now these 
procedures are required at the time a subject exits the study 
(discontinues or end-of-study).
Synopsis; Table 1; 
15.3.2; 15.3.3; 
15.4.9
Text was clarified to indicate the follow up telephone contact is 30 
days from last dose of study drug (clarified from “discharge” which 
can be interpreted as discharge from the inpatient clinic).
Synopsis; Table 1;
15.1; 15.2; 15.3.1; 
15.3.2; 15.5.6; 
17.2.11; 17.3.2; 
Appendices 9 & 10
Added Columbia Suicide Severity Rating Scale per FDA 
requirement because lofexidine is active in the central nervous 
system, is being developed for a psychiatric indication, and a 
prospective assessment for suicidal thoughts and behavior was not 
included in previous clinical trials.
Synopsis; 17.2.6
Clarified tertiary/exploratory endpoint regarding subject treatment 
status to be 30 days after last dose, not 30 days post-discharge.
Synopsis; Table 1; 
15.3.1; 15.5.4.1;
15.5.5
Text was clarified to reflect that clinical laboratory testing and 
physical examinations will be done at the end of double-blind 
dosing and before initiating open-label dosing rather than at 
“discharge.”
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Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 3 of 80
Location
Modification/Rationale
Synopsis; Table 1; 
15.5.4.5
Additional PK blood sample collections were added on Days 3 and 
6 to provide data at approximate steady state.
5
Abbreviations list was updated.
11.2.2; 15.5.4.2
The method for testing for syphilis was updated to the central 
laboratory’s current method for syphilis testing.
12.3
Third paragraph was clarified to allow dispensing of 1 to 2 days of 
medication at each daily clinic visit during the open-label phase 
(Days 8-14) to accommodate flexible scheduling of clinic visits.
Fourth paragraph was clarified that study medications could be 
dispensed by the site pharmacist “or designee” because not all study 
sites have an on-site pharmacist.
12.5
Several administrative clarifications were made to the study drug 
labels.
12.6
Text was clarified that investigational agents could be stored at the 
dispensing pharmacy “or site.”
12.8
Text was revised to improve clarity.
13.2.2
Text was clarified to indicate that dose-hold criteria apply to 
pre-dose vital signs.
13.2.3
Sixth and seventh bullets were revised for consistency with subject 
discontinuation (Section 14.5.1).
13.4
Text was clarified to allow an “estimate” of the total number of 
tobacco products used daily during Days 1-14.
14.1
First paragraph was clarified to indicate that subjects would be 
inpatient at a hospital “or clinic” because not all study sites are 
located in a hospital.
Second paragraph, second sentence was clarified that collection of 
demographic information is required before site personnel access 
the IWRS to obtain a unique subject number.
14.3.1
First sentence was clarified to indicate that subjects would be 
inpatient at a hospital “or clinic” because not all study sites are 
located in a hospital.
Fourth sentence was clarified regarding when a subject was 
considered enrolled in the study.
14.3.2
Sentence was added to first paragraph regarding a subject’s final 
eligibility requirements.
Second paragraph was modified to reflect that the IWRS will assign 
a “kit number” number for drug dispensing according to the 
randomization scheme and that the subject’s screening number will 
be used on all source documents and eCRFs. 
14.4
Text was clarified to remove stipulation that subjects will receive 
their compensation for study participation at the end of the study, 
thus providing individual study sites flexibility per their standard or 
IRB-required payment schedule.
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Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
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Page 4 of 80
Location
Modification/Rationale
14.5.1
Item #4 was revised to specify only during Days 1-7 of the study, 
because subjects with a positive urine drug screen during Days 8-14
will be allowed to remain in the open-label phase of the study as
long as their continued participation is deemed safe by investigator.
14.6
First paragraph was added to allow a single administration of a 
short-acting opioid to keep a subject reasonably comfortable in the 
event the subject is admitted to the inpatient study unit the day 
before Baseline (i.e., Day -1).
Last paragraph was added to allow psychosocial therapy per 
standard of care at individual study sites.
15
Table 1 was modified to provide a separate column for Study 
Discontinuation/End of Study procedures and table footnotes 
updated accordingly.
15.3.3
Section was added to clarify what procedures/assessments will be 
done at discontinuation from the study (after last dose of study 
medication).
15.4.1
Text was clarified to indicate that for each daily SOWS-Gossop 
evaluation, subjects should consider their symptoms over the last 
24-hour period or since the last time they took this test.
15.4.2
Third paragraph was clarified to provide ambient room temperature 
range (67-75°F) during assessment of OOWS-Handelsman.
15.5.3
Text was clarified to indicate duplicate 12-lead ECGs would be 
done at discontinuation from the study during Days 8-14.
15.5.4.1
Table 5 was updated for consistency with the laboratory tests 
conducted routinely by the central laboratory.
15.5.4.2
Abbreviations for hepatitis analytes were revised for consistency 
with the central laboratory’s abbreviations for these tests.
16.7
Second paragraph, second sentence was revised to indicate that a
clinically significant finding on C-SSRS will be reported as an 
adverse event.
18.1; 18.2; 18.3
Clarified which CRO 
 is responsible 
for data collection, eCRFs, and data analysis
Appendix 1
SOWS-Gossop scale was replaced with an exact copy of the scale 
the subject will complete.
Appendix 2
OOWS-Handelsman text was corrected to reflect that subjects will 
be observed for 5 minutes (not 10 minutes).
Appendix 3
MCGI - Subject version was replaced with an exact copy of the 
scale the subject will complete.
Appendix 4
Visual Analog Scale for Efficacy was replaced with an exact copy 
of the scale the subject will complete.
Appendix 8
Outpatient Vital Signs Diary was replaced with an exact copy of the 
diary the subject will complete.  Also, correction was made to 
indicate that vital signs will be recorded after 3 minutes (not 
5 minutes) of rest (sitting or lying down) and 3 minutes standing.
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Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 5 of 80
Prior changes made in Amendment No. 01 are listed below.
Location
Modification/Rationale
Title Page,
Synopsis
Protocol title was clarified to better reflect the 2-part design of the 
study.
Synopsis, 
11.2.1, 11.2.2
Inclusion criterion #2, exclusion criterion #4, and exclusion criterion #9
were modified to use the Mini International Neuropsychiatric Interview 
(M.I.N.I.) rather than the Structured Clinical Interview for DSM-IV-TR 
Axis I Disorders (SCID) to establish the appropriate dependence 
diagnosis on opioids, exclude other drug dependency, and determine the 
absence of major psychiatric disorders.  The M.I.N.I. is a validated 
scale (Sheehan et al., 1998) and is used commonly in clinical practice 
and research studies.
Synopsis
Number of study sites was updated from 10 to approximately 12.
Synopsis;
6.6; 14.3.4; 
17.2.5; 17.2.8.2
The definition of completion status was clarified to: whether a subject
receives at least one dose of study medication on Day 7 and completes 
the 3.5-hour post-dose Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop) assessment on Day 7.
Synopsis; 9; 
10.2
Text was added to allow additional study sites (up to 20) in the event 
that the enrollment rate is unsatisfactory.
Synopsis; 
11.2.1
Inclusion criterion #8 was removed because completion of the 
Objective Opiate Withdrawal Scale of Handelsman (OOWS-
Handelsman) at baseline is covered in inclusion criterion #4.
Synopsis; 
11.2.2; 13.2.3; 
15.5.2; 15.5.3; 
17.2.11
Text was modified to use QTc (Fridericia) instead of QTc (Bazett) for 
safety monitoring/subject termination purposes because QTcF is now 
more commonly used when correcting for low pulse rates.
Synopsis; 
15.3.1; 15.3.2;
15.4.5; 17.2.6;
17.2.8.4; 17.3.1
Clinical Opiate Withdrawal Scale (COWS) was added as an efficacy 
measure for consistency with efficacy measures evaluated in other 
lofexidine clinical trials.
Synopsis, 
17.2.6, 17.2.8.8
Text was added to allow for the potential analysis of single items 
(e.g., sweating, anxiety) from the OOWS-Handelsman and COWS that 
are not included in the SOWS-Gossop, as well as area under the curve 
(AUC) based on COWS scores from Days 1 through 7.
Synopsis; 
17.2.6; 17.2.8.7
Status of detoxification on Day 7 or early termination was added as a 
tertiary/exploratory endpoint because these data are being collected.
Synopsis; 
17.3.1
The tertiary endpoint (Days 8-14) was clarified for number of days 
required to complete detoxification “as assessed by the Site 
Investigator.”
5
Abbreviation list was updated.
6.1
Text was updated for consistency with other more current documents.
6.4
Text was updated to account for more current safety information.
10.1
Second paragraph was clarified regarding subject eligibility for 
treatment in the open-label part of the study.
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Location
Modification/Rationale
12.4
First paragraph was clarified to indicate the biostatistician will be 
blinded to medication assignment groups and that the finger-prick 
pharmacokinetic samples from placebo subjects will not be analyzed.
The third and fourth paragraphs were removed.  A cross-reference to 
Section 14.3.5 was added, which details requirements should 
unblinding become necessary for the safety of the subject.
12.5
Text was clarified regarding labeling of investigational agents.
13.2.1
Second paragraph was clarified to require the Site Investigator’s 
rationale for his/her decision to continue subject’s treatment in either an 
inpatient or outpatient setting.
13.2.2
Dose-hold criteria was clarified for symptoms of hypotension and/or 
bradycardia and a statement was added regarding the need to record all 
instances of dose-holds in source documents.
14.3.2
Second paragraph was clarified to indicate randomization will be done 
using an Interactive Voice Response System (IVRS) or an Interactive 
Web Response System (IWRS) managed by the CRO.
14.3.5
First and last paragraphs were clarified regarding breaking the study 
blind.
14.5.1
First paragraph was clarified regarding when subjects “may” or “must” 
be terminated from the study. Also, Item 8 was clarified regarding 
termination requirements for missed doses.
14.5.2
Item 2 was clarified regarding termination requirements for persistent 
symptomatic hypotension, either not responding to bed rest or fluids.
15
Table 1 was modified to:
x Add SOWS-Gossop at baseline.
x Add COWS at screening, baseline, and each day during treatment 
(Days 1-7 and Days 8-14).
x Add OOWS-Handelsman at screening.
x Replace the SCID with the M.I.N.I.
x To allow subjects to record the 3.5-hour post-dose vital signs 
measurements using a portable digital blood pressure machine if they 
are being treated on an outpatient basis and cannot stay in the clinic 
for this required post-dose measurement (see footnote j).
15.1
Screening assessments were clarified to include alcohol history.
Text was revised to use the M.I.N.I. rather than SCID.
15.2
SOWS-Gossop was added as a required baseline assessment so it can be 
used as a covariate in the analysis.
15.4.1
First paragraph was clarified to provide a window (± 10 minutes) for 
the 3.5-hour post first daily dose recording of the SOWS-Gossop.  Also, 
text was clarified to indicate that for each daily evaluation, subjects 
should consider their symptoms over the last 24-hour period.
15.4.8;
Appendix 6
Text was clarified regarding what should be recorded as withdrawal-
related adverse events.
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Location
Modification/Rationale
15.5.2
Second paragraph was clarified to provide a window (± 15 minutes) for 
the required 3.5-hour post-dose measurement of vital signs.
Third paragraph, which pertains to the open-label part of the study 
(Days 8-14), was clarified to provide a window (± 30 minutes) for the 
required 3.5-hour post-dose measurement of vital signs.  Also, a 
provision was added to allow subjects to record the 3.5-hour post-dose 
measurements using a portable digital blood pressure machine if they 
are being treated on an outpatient basis and cannot stay in the clinic for 
this required post-dose measurement.
15.5.3
Text was clarified to provide a window (± 15 minutes) for the required 
ECG recordings.
15.5.3
Text was clarified that an on-site qualified physician (rather than a 
cardiologist) will evaluate ECG tracings if there is significant 
abnormality.
16.2
Title of subsection and text was clarified to remove reference to FDA 
Form 3454 because the Sponsor (US WorldMeds) will provide a 
Financial Disclosure form (internal template) to each site for signature.
16.6.1
Text was revised to reflect the use of the National Institute on Drug 
Abuse (NIDA) Data and Safety Monitoring Board (DSMB) for this 
study.
16.8.1
Section was added to further clarify SAE requirements.
16.9
Section was added for Overdose.
17.2.8.1
Statistical methods were revised to use 4 disposition strata in assessing 
SOWS-Gossop AUC(1-7). Also, Item 2 (Modeling) was revised to 
include baseline SOWS-Gossop score as a covariate in the analysis.
18.1; 18.4;
18.5.2
Text was clarified to indicate that all data will be entered electronically 
(eCRFs) and no paper CRFs will be used.
18.2
Text was clarified regarding electronic data capture requirements.
22
References were added for COWS (Wesson and Ling, 2003) and for the 
M.I.N.I. (Sheehan et al., 1998; Medical Outcomes Systems, M.I.N.I.
version 6.0).
Appendices 1-5
Scales used to assess efficacy were added as appendices.
Appendix 6
Item E was clarified to indicate where SAEs are to be reported.
Appendix 8
Outpatient Vital Signs Diary was added so subjects who cannot stay in 
the clinic for the 3.5-hour post-dose vital signs measurement can 
complete this measurement using a portable digital blood pressure 
machine and record the results in the diary.
Several administrative clarifications were made in Amendment No. 1, with updates 
throughout as appropriate:
x
 as the central IRB;
x
 as the Clinical Research Organization (CRO);
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x
as the pharmacy coordinating center/central pharmacy;
x
as the central laboratory for analysis of blood and 
urine samples; and
x
 as the ECG core lab.
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2 
SIGNATURE PAGE 
By signing below, US WorldMeds, LLC and the investigator indicate approval of this 
protocol as well as assurance that this study will be conducted according to the procedures 
described in the protocol Good Clinical Practices, and a11 applicable regulatory 
requirements. 
Pr·otocol Approval: 
Signature: 
Name (print): 
Medical Director 
US WorldMeds, LLC 
Date: M/-1'1 7 	 e f 3 
Investigator Agreement: I have read the protocol and agree to conduct the study as 
outlined herein. 
Signatu1·e: 
Date: ------
Name (print): 
Confidential Inf01mation 
Page 9 of80 
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3 SYNOPSIS
Title
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 
Efficacy, Safety, and Dose-Response Study of Lofexidine in the Treatment 
of Opioid Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose 
Lofexidine Treatment (Days 8-14)
Objective
To investigate the efficacy, safety, and dose-response of lofexidine 
hydrochloride (2.4 mg or 3.2 mg per day) in reducing withdrawal signs and 
symptoms and facilitating completion of detoxification/extending treatment 
retention in subjects undergoing detoxification from short-acting opioids in 
a double-blind inpatient setting (Days 1-7) followed by an open-label 
inpatient/outpatient setting (Days 8-14).
Study Design
Two-part, multicenter study in the United States.  The first part of the study 
will use an inpatient, randomized, double-blind, placebo-controlled design, 
which will be followed by a second part, an open-label, continuation 
treatment.
The first part of the study will consist of 7 days of inpatient treatment with 
lofexidine 2.4 mg total daily dose (0.6 mg QID), lofexidine 3.2 mg total 
daily dose (0.8 mg QID), or matching placebo (Days 1-7). During the 
second part of the study (Days 8-14), all subjects, regardless of their 
treatment assignment (which will remain double-blinded), who successfully 
complete Days 1-7, will be eligible to receive open-label, variable dose 
lofexidine treatment as determined by the Site Investigator.  Subjects can be 
treated as inpatients or outpatients during Days 8-14, depending on the 
wishes of the Site Investigator and the subject, for up to an additional 
7 days. No subject will receive lofexidine for more than 14 days total from 
the onset of abstinence.
Sites
~12 (Target: ≥3-4 subjects/site/month. Recruitment time: 12-15 months)
(In the event that the enrollment rate is unsatisfactory, additional centers 
will be added for a total site base of up to 20.)
Inclusion
Criteria
1.
Be male or female at least 18 years of age.
2.
Have current dependence, according to the Mini International
Neuropsychiatric Interview (M.I.N.I.), on any opioid with a half-life
similar to heroin or morphine, including Vicodin®, Lortab®, Lorcet®,
Percocet®, Percodan®, Tylox®, or Hydrocodone (by any route of
administration), or oxycodone (oxycodone and oxycodone time-
released formulation when crushed and snorted, injected or swallowed
after chewing).
3.
Be seeking treatment for opioid dependence.
4.
Have a score ≥2 on the Objective Opiate Withdrawal Scale 
(OOWS-Handelsman) at Baseline.
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Inclusion
Criteria
(continued)
5.
Have reported use of heroin, morphine, or any opioid with a half-life
similar to heroin or morphine for at least 21 of the past 30 days.
6.
Urine toxicology screen positive for opioids and negative for
methadone or buprenorphine.
7.
If female and of childbearing potential, subject must agree to use of
one of the following methods of birth control:
x oral contraceptives;
x patch;
x barrier (diaphragm, sponge or condom) plus spermicidal
preparations;
x intrauterine contraceptive system;
x levonorgestrel implant;
x medroxyprogesterone acetate contraceptive injection;
x complete abstinence from sexual intercourse;
x hormonal vaginal contraceptive ring; or
x surgical sterilization or partner sterile (must have documented 
proof).
8.
Be able to verbalize understanding of the consent form, able to provide
written informed consent, verbalize willingness to complete study
procedures and pass the study consent quiz with 100% accuracy (if
necessary, quiz may be administered more than one time).
Exclusion 
Criteria
1.
Be a female subject who is pregnant or lactating.
2.
Have self-reported use of methadone or buprenorphine in the past
14 days.
3. Have serious medical illnesses including, but not limited to:
x seizures, or those who have received anticonvulsant therapy during
the past 5 years;
x pancreatic disease such as insulin-dependent diabetes;
x liver disease that requires medication or medical treatment, and/or 
aspartate aminotransferase or alanine aminotransferase levels greater 
than 5 times the upper limit of normal;
o an infectious disease panel for hepatitis will be performed as an aid
to determine if the prospective subject has been exposed to a
hepatitis virus; positive hepatitis results do not exclude a
prospective subject from participation unless there is an indication
of active liver disease; and
x gastrointestinal or renal disease, which would significantly impair 
absorption, metabolism or excretion of study drug, or would require 
medication or medical treatment.
4. Have a psychiatric disorder, based on the M.I.N.I., including but not
limited to dementia or any disorder that, in the opinion of the study
physician requires ongoing treatment that would make study
participation unsafe or which would make treatment compliance
difficult.
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Exclusion 
Criteria 
(continued)
5. Have self-reported acquired immune deficiency syndrome (AIDS) or
self-reported human immunodeficiency virus (HIV) positive status and
taking retroviral medications currently or within the past 4 weeks.
6. Abnormal cardiovascular exam at screening and before randomization,
including any of the following:
x clinically significant abnormal electrocardiogram (ECG) (e.g., second
or third degree heart block, uncontrolled arrhythmia, or QTcF interval 
greater than 450 msec for males and greater than 470 msec for 
females);
x heart rate less than 55 bpm or symptomatic bradycardia;
x systolic blood pressure less than 95 mmHg or symptomatic 
hypotension;
x diastolic blood pressure less than 65 mmHg;
x blood pressure greater than 155/95 mmHg; and
x prior history of myocardial infarction.
7. Have clinically significant abnormal laboratory values.
8. Requiring any of the following medications currently or within the past
4 weeks:  psychotropics (including sedatives/hypnotics, antidepressants,
neuroleptics), prescription analgesics (excluding those listed in inclusion
criterion #2 above), anticonvulsants, antihypertensives, antiarrhythmics,
antiretroviral, and cholesterol lowering medications.  Nicotine
replacement therapy (patch, inhaler, gum, or nasal spray) is allowed for
nicotine-dependent subjects. Note:  Use of a short-acting
benzodiazepine (e.g., oxazepam) for insomnia during Days 8-14 will not
disqualify a subject.
9. Current dependence (based on the M.I.N.I.) on any psychoactive
substance (other than that listed in inclusion criterion #2, caffeine, or
nicotine) that requires detoxification.
10. Have donated blood within the last 8 weeks.
11. Have participated in an investigational drug study within the past
3 months.
12. Have such “poor” veins that even a single venipuncture cannot be
obtained during screening.
13. Have active tuberculosis (positive tuberculin test and/or confirmatory
diagnostic chest x-ray).
14. Have active syphilis.
N
A sufficient number of subjects will be screened to randomize 600 subjects 
in a 3:3:2 ratio (225 in each lofexidine group and 150 in the placebo group)
at approximately 12 study sites in the US.  The total number of subjects 
randomized at each site will depend on subject availability and will likely
not be evenly distributed at all sites.
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Primary 
Endpoint
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
x Area under the curve (AUC) based on Short Opiate Withdrawal Scale 
of Gossop (SOWS-Gossop) scores from Days 1 through 7.
Secondary 
Endpoint
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
x Completion status (whether a subject receives at least one dose of 
study medication on Day 7 and completes the 3.5-hour post-dose
SOWS-Gossop assessment on Day 7).
Tertiary/
Exploratory 
Endpoints
Days 1-7:  Randomized, Double-Blind, Placebo-Controlled Treatment
x SOWS-Gossop, OOWS-Handelsman, Modified Clinical Global 
Impression (MCGI [Subject and Rater]), Visual Analog Scale for 
Efficacy (VAS-E ), and Clinical Opiate Withdrawal Scale (COWS)
scores on Days 1, 2, 3, 4, 5, 6, and 7;
x Retention analysis (time to removal from study treatment) over the 
7 inpatient days; 
x Status of detoxification on Day 7 or early termination as assessed by 
the Site Investigator;
x Concomitant medication analysis;
x Withdrawal-related adverse event analysis; 
x Evaluation of subject treatment status 30 days after last dose; and
x In addition, single items (e.g., sweating, anxiety) from the OOWS-
Handelsman and COWS that are not included in the SOWS-Gossop 
may be analyzed, as may AUC based on COWS scores from Days 1
through 7.
Days 8-14: Open-Label, Continuation Treatment
x Descriptive evaluation of SOWS-Gossop, OOWS-Handelsman, MCGI 
(Subject and Rater), VAS-E, and COWS;
x Duration of exposure;
x Number/proportion of subjects successfully completing detoxification 
as assessed by the Site Investigator;
x Distribution of number of days required to complete detoxification as 
assessed by the Site Investigator;
x Average daily dose of lofexidine; and
x Concomitant medications.
Duration
21 days (maximum duration per subject, including screening)
Visits
All subjects will undergo screening up to 7 days before study admission.
Days 1-7:  Randomized, Double-Blind, Placebo-Controlled Treatment
x Inpatient confinement on Days 1 through 7
Days 8-14: Open-Label, Continuation Treatment
x Inpatient or daily for up to 7 days if outpatient
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Efficacy 
Assessments
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
The following efficacy assessments will be performed daily at estimated 
time of maximum plasma concentration (i.e., 3.5 hours after the first dose):
x SOWS-Gossop;
x OOWS-Handelsman;
x MCGI (Subject and Rater);
x VAS-E;
x COWS;
x Concomitant medication use; and
x Completion of detoxification as assessed by the Site Investigator (at 
completion of Inpatient Treatment on Day 7 only or, if applicable, 
early termination during Days 1-7).
Days 8-14: Open-Label, Continuation Treatment
The following efficacy assessments will be performed daily before dosing:
x SOWS-Gossop;
x OOWS-Handelsman;
x MCGI (Subject and Rater);
x VAS-E;
x COWS;
x Concomitant medication use; and
x Completion of detoxification as assessed by the Site Investigator.
Safety 
Assessments
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
The following safety assessments will be performed daily unless otherwise 
specified below:
x Occurrence, seriousness, severity, and causality assessment of 
adverse events (AEs);
x Vital signs (blood pressure and pulse at rest [sitting or recumbent, if 
required, for treatment of an AE] and standing; respiration, and 
temperature) before every dose and 3.5 hours after administration of 
study medication at 8 AM, 1 PM, and 6 PM;
x 12-lead ECGs (in duplicate) will be done before the first daily dose, 
pre-1 PM dose, at 4 PM, and at 5 PM on Days 1 and 7; before the first 
daily dose only on Days 2 and 4; and, if applicable, early termination 
during Days 1-7;
x Clinical laboratory tests as clinically warranted and at the end of 
double-blind dosing and before initiating open-label dosing or early 
termination during Days 1-7;
x Finger prick blood sample for pharmacokinetic (PK) analysis will be 
collected concurrently with each scheduled ECG during Days 1-7, as 
well as on Days 3 and 6 at 9 PM and 10 PM (3 and 4 hours, 
respectively, after 6 PM dose);
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Safety 
Assessments 
(continued)
x
Physical examination at Baseline (update of Screening exam), a 
complete exam 3 to 4 hours after randomization on Day 1 and at the 
end of double-blind dosing and before initiating open-label dosing or 
early termination during Days 1-7; and
x
Columbia Suicide Severity Rating Scale (C-SSRS) at Baseline 
(before dosing on Day 1) and 3.5 hours after the first dose (8 AM) on 
Days 1-7, or, if applicable, early termination during Days 1-7.
In addition, qualitative urine drug screening (by on-site use of “dipsticks”) 
will be done at least every other day to monitor for contraband.
Days 8-14: Open-Label, Continuation Treatment
The following safety assessments will be performed daily unless otherwise 
specified below:
x Occurrence, seriousness, severity, and causality assessment of AEs;
x Vital signs (blood pressure and pulse at rest (sitting or recumbent, if 
required, for treatment of an AE) and standing at least once daily
before dosing and 3.5 hours after dosing on Days 8-13 and once 
before a dose on Day 14 or, if applicable, at discontinuation from the 
study;
x 12-lead ECGs (in duplicate) will be done before the first daily dose 
and at 11:30 AM on Day 8; once pre-dose on Day 14 or, if applicable, 
at discontinuation from the study;
x Clinical laboratory tests as clinically warranted and at discontinuation
from the study; 
x Complete physical examination as clinically warranted and at 
discontinuation from the study; and
x Pregnancy test at discontinuation from the study.
x C-SSRS daily before dosing or, if applicable, at discontinuation from 
the study.
Qualitative urine drug screening (by on-site use of “dipsticks”) will be done 
at least every other day to monitor for illicit drug use.
A follow-up telephone contact will be made 30 days after the subject’s last 
dose of study drug for an adverse event evaluation and an evaluation of the 
subject’s current treatment status (e.g., relapse, current psychosocial 
treatment, successful entry into a methadone, buprenorphine, or naltrexone 
program).
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4 TABLE OF CONTENTS
1 
PROTOCOL AMENDMENT SUMMARY...................................................................2 
2 
SIGNATURE PAGE.......................................................................................................9 
3 
SYNOPSIS....................................................................................................................10 
4 
TABLE OF CONTENTS..............................................................................................16 
5 
ABBREVIATIONS ......................................................................................................21 
6 
BACKGROUND AND SIGNIFICANCE ....................................................................23 
6.1 
Opioid Dependence ..................................................................................................23 
6.2 
Lofexidine Hydrochloride ........................................................................................23 
6.3 
Efficacy of Lofexidine .............................................................................................24 
6.4 
Safety of Lofexidine.................................................................................................25 
6.5 
Rationale for Dose Selection and Regimen..............................................................26 
6.6 
Rationale for Outcome Measures.............................................................................26 
7 
STUDY OBJECTIVES.................................................................................................27 
8 
STUDY SPONSOR ......................................................................................................27 
9 
STUDY SITES AND INVESTIGATORS ...................................................................27 
10 
INVESTIGATIONAL PLAN .......................................................................................27 
10.1 
Overall Design..........................................................................................................27 
10.2 
Number of Subjects..................................................................................................28 
10.3 
Duration of Study .....................................................................................................28 
11 
SELECTION OF STUDY POPULATION ..................................................................28 
11.1 
Population Base........................................................................................................28 
11.2 
Study Entrance Requirements ..................................................................................29 
11.2.1 
Inclusion Criteria.................................................................................................29 
11.2.2 
Exclusion Criteria................................................................................................29 
11.3 
Screening Failures ....................................................................................................31 
12 
INVESTIGATIONAL AGENTS..................................................................................32 
12.1 
Lofexidine Hydrochloride ........................................................................................32 
12.2 
Placebo .....................................................................................................................32 
12.3 
Dispensing Investigational Agents...........................................................................32 
12.4 
Blinding Plan............................................................................................................33 
12.5 
Labeling....................................................................................................................33 
12.6 
Storage......................................................................................................................35 
12.7 
Record of Administration.........................................................................................35 
12.8 
Used/Unused Supplies..............................................................................................35 
12.9 
Contraindications .....................................................................................................35 
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13 
TREATMENT PLAN ...................................................................................................35 
13.1 
Investigational Agents..............................................................................................35 
13.2 
Dose Administration ................................................................................................36 
13.2.1 
Administration of Doses......................................................................................36 
13.2.2 
Dose-Hold Criteria ..............................................................................................37 
13.2.3 
Discontinuation Criteria ......................................................................................37 
13.3 
Treatment Compliance .............................................................................................38 
13.4 
Nicotine Replacement Therapy................................................................................38 
14 
STUDY PROCEDURES ..............................................................................................38 
14.1 
Subject Recruitment and Consent ............................................................................38 
14.2 
Screening..................................................................................................................39 
14.3 
Treatment Phase .......................................................................................................39 
14.3.1 
Baseline ...............................................................................................................39 
14.3.2 
Subject Randomization........................................................................................39 
14.3.3 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment) ............40 
14.3.4 
Days 8-14 (Open-Label, Continuation Treatment) .............................................40 
14.3.5 
Maintaining and Breaking the Blind ...................................................................41 
14.4 
Subject Reimbursement............................................................................................41 
14.5 
Study Discontinuation..............................................................................................42 
14.5.1 
Subject Discontinuation.......................................................................................42 
14.5.2 
Cardiovascular Events Requiring Subject Discontinuation From Study ............43 
14.5.3 
Trial Discontinuation...........................................................................................43 
14.6 
Concomitant Therapy...............................................................................................44 
15 
CLINICAL EVALUATIONS.......................................................................................45 
15.1 
Screening Assessments ............................................................................................49 
15.2 
Baseline Assessments...............................................................................................49 
15.3 
Assessments During Treatment................................................................................50 
15.3.1 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment) ............50 
15.3.2 
Days 8-14 (Open-Label, Continuation Treatment) .............................................51 
15.3.3 
Study Discontinuation/End of Study...................................................................52 
15.4 
Efficacy Assessment Methods .................................................................................53 
15.4.1 
Short Opiate Withdrawal Scale (SOWS-Gossop) ...............................................53 
15.4.2 
Objective Opiate Withdrawal Scale (OOWS-Handelsman)................................53 
15.4.3 
Modified Clinical Global Impressions Scale (MCGI).........................................54 
15.4.4 
Visual Analog Scale for Efficacy (VAS-E).........................................................55 
15.4.5 
Clinical Opiate Withdrawal Scale (COWS) ........................................................55 
15.4.6 
Assessment of Completion of Detoxification......................................................56 
15.4.7 
Concomitant Medication Use ..............................................................................56 
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15.4.8 
Withdrawal-Related Adverse Events ..................................................................56 
15.4.9 
Subject Treatment Status 30 Days After Last Dose ............................................56 
15.5 
Safety Assessment Methods.....................................................................................56 
15.5.1 
Adverse Events....................................................................................................56 
15.5.2 
Vital Signs ...........................................................................................................57 
15.5.3 
12-Lead Electrocardiograms ...............................................................................58 
15.5.4 
Clinical Laboratory Evaluations..........................................................................59 
15.5.4.1 
Standard Laboratory Tests..............................................................................59 
15.5.4.2 
Infectious Disease Panel and Syphilis Tests...................................................60 
15.5.4.3 
Urine Toxicology Screening...........................................................................61 
15.5.4.4 
Pregnancy Test................................................................................................61 
15.5.4.5 
Pharmacokinetic Sampling .............................................................................61 
15.5.5 
Physical Examination ..........................................................................................61 
15.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS)............................................61 
15.6 
Other Assessments ...................................................................................................62 
15.6.1 
Prior Medications ................................................................................................62 
15.6.2 
Concomitant Medication Administration ............................................................62 
16 
REGULATORY AND REPORTING REQUIREMENTS...........................................62 
16.1 
Good Clinical Practices............................................................................................62 
16.2 
FDA Form 1572 and Financial Disclosure ..............................................................62 
16.3 
Institutional Review Board Approval ......................................................................63 
16.4 
Informed Consent/HIPAA Authorization ................................................................63 
16.5 
Drug Accountability.................................................................................................63 
16.6 
Outside Monitoring ..................................................................................................64 
16.6.1 
Data and Safety Monitoring Board (DSMB).......................................................64 
16.6.2 
Medical Monitor..................................................................................................64 
16.6.3 
Clinical Monitors.................................................................................................64 
16.7 
Adverse Event Reporting .........................................................................................65 
16.8 
Serious Adverse Events (SAEs)...............................................................................65 
16.8.1 
Clarification of Serious Adverse Events .............................................................66 
16.9 
Overdose...................................................................................................................67 
16.10 
Pregnancy .................................................................................................................67 
17 
STATISTICAL APPROACH .......................................................................................68 
17.1 
General Considerations ............................................................................................68 
17.2 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment).................68 
17.2.1 
Analysis Populations ...........................................................................................68 
17.2.2 
Demographics and Baseline Characteristics .......................................................68 
17.2.3 
Subject Disposition..............................................................................................69 
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17.2.4 
Primary Efficacy Endpoint ..................................................................................69 
17.2.5 
Secondary Efficacy Endpoint ..............................................................................69 
17.2.6 
Tertiary/Exploratory Endpoints...........................................................................69 
17.2.7 
Control of the False Positive Rate and Statistical Testing Strategy ....................69 
17.2.8 
Statistical Methods for Efficacy ..........................................................................70 
17.2.8.1 
SOWS-Gossop AUC(1-7) ..............................................................................70 
17.2.8.2 
Completion Status...........................................................................................71 
17.2.8.3 
SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7................................................71 
17.2.8.4 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS.........72 
17.2.8.5 
Retention Analysis (Time to Removal from Study Treatment)......................72 
17.2.8.6 
Concomitant Medication Analysis .................................................................72 
17.2.8.7 
Status of Detoxification on Day 7 or Early Termination as Assessed by 
the Site Investigator ........................................................................................72 
17.2.8.8 
Single Items from the OOWS-Handelsman and COWS, and COWS 
AUC(1-7)........................................................................................................72 
17.2.9 
Power Calculations..............................................................................................73 
17.2.10 Subgroup Analyses..............................................................................................73 
17.2.11 Safety Measures...................................................................................................73 
17.3 
Days 8-14 (Open-Label, Continuation Treatment) ..................................................73 
17.3.1 
Assessment of Effectiveness ...............................................................................74 
17.3.2 
Assessment of Safety...........................................................................................74 
18 
DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) ............................75 
18.1 
Data Collection.........................................................................................................75 
18.2 
Electronic Data Capture ...........................................................................................75 
18.3 
Data Analysis ...........................................................................................................75 
18.4 
Study Documentation and Records Retention .........................................................76 
18.5 
Confidentiality..........................................................................................................76 
18.5.1 
Confidentiality of Data........................................................................................76 
18.5.2 
Confidentiality of Subject Records .....................................................................76 
19 
PUBLICATIONS OF THE STUDY RESULTS ..........................................................77 
20 
PROTOCOL ADHERENCE AND AMENDMENTS..................................................78 
21 
QUALITY CONTROL AND QUALITY ASSURANCE............................................78 
22 
REFERENCES..............................................................................................................78 
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TABLES
Table 1. Schedule of Study Assessments ...............................................................................46 
Table 2. SOWS-Gossop Scoring Method...............................................................................53 
Table 3. OOWS-Handelsman Scoring Method......................................................................54 
Table 4. MCGI Scoring Method.............................................................................................55 
Table 5. Hematology, Chemistry, and Urinalysis Tests.........................................................60 
APPENDICES
Appendix 1 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop)
Appendix 2 
Objective Opiate Withdrawal Scale of Handelsman (OOWS-Handelsman) 
Appendix 3 
Modified Clinical Global Impression (MCGI)
Appendix 4 
Visual Analog Scale for Efficacy (VAS-E)
Appendix 5 
Clinical Opiate Withdrawal Scale (COWS)
Appendix 6 
Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events
Appendix 7 
Procedure for Applying for a Certificate of Confidentiality
Appendix 8 
Outpatient Vital Signs Diary
Appendix 9 
Columbia Suicide Severity Rating Scale (C-SSRS) Baseline Version 
Appendix 10 Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version
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5 ABBREVIATIONS 
Abs
Absolute
AE(s)
Adverse Event(s)
AIDS
Acquired Immune Deficiency Syndrome
ALT/SGPT
Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase
Anti-HCV
Hepatitis C Virus Antibody
aPTT
Activated Partial Thromboplastin Time
AUC
Area Under the Concentration-Time Curve
AST/SGOT
Aspartate Aminotransferase/Serum Glutamic-Oxaloacetic 
Transaminase
BP
Blood Pressure
bpm
beats per minute
BUN
Blood Urea Nitrogen
CAP
College of American Pathologists
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Act of 1988
CO2
Carbon Dioxide
COWS
Clinical Opiate Withdrawal Scale
CRF(s)
Case Report Form(s)
CRO
Clinical Research Organization
C-SSRS
Columbia Suicide Severity Rating Scale
DAWN
Drug Abuse Warning Network
DBP
Diastolic Blood Pressure
DHHS
Department of Health and Human Services
DSMB
Data and Safety Monitoring Board
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders - Fourth 
Edition
ECG
Electrocardiogram
eCRF(s)
Electronic Case Report Form(s)
EDC
Electronic Data Capture
EIA
Automated Enzyme Immunoassay
FDA
Food and Drug Administration
FWE
Familywise Error Rate
GCP
Good Clinical Practices
GGTP
Gamma-Glutamyl Transpeptidase
HBcAb
Hepatitis B Core Antibody
HBsAb
Hepatitis B Surface Antibody
HBsAg
Hepatitis B Surface Antigen
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonization
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intent-To-Treat
LDH
Lactate Dehydrogenase
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IWRS
Interactive Web Response System
MCGI
Modified Clinical Global Impression
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MHOWS
Modified Himmelsbach Opiate Withdrawal Scale
M.I.N.I.
Mini International Neuropsychiatric Interview
mITT
Modified Intent-To-Treat
mmHg
Millimeters of Mercury
msec
Millisecond
NDA
New Drug Application
NIMH
National Institute of Mental Health
OOWS-Handelsman
Objective Opiate Withdrawal Scale of Handelsman
PK
Pharmacokinetic
PPD
Purified Protein Derivative (skin test for tuberculosis)
PRN
As Needed
PT
Prothrombin Time
QID
Four Times Daily
QT
QT interval of an electrocardiogram
QTc
Corrected QT interval
QTcB
Corrected QT interval – Bazett’s method
QTcF
Corrected QT interval – Fridericia’s method
QTcI
Individually corrected QT interval
RBC
Red Blood Cell
RDW
Red Blood Cell Distribution Width
RPR
Rapid Plasma Reagin
SAE(s)
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SOWS-Gossop
Short Opiate Withdrawal Scale of Gossop
T4
Free Thyroxine
Tmax
Time of Maximum Plasma Drug Concentration
TPPA
Treponema Pallidum Particle Agglutination Assay
TSH
Thyroid-Stimulating Hormone
UDS
Urine Drug Screening
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
USWM
US WorldMeds, LLC
VAS-E
Visual Analog Scale for Efficacy
WBC
White Blood Cell
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7 STUDY OBJECTIVES
The primary objective of this study is to investigate the efficacy, safety, and dose-response of 
lofexidine (2.4 mg or 3.2 mg per day) in reducing withdrawal signs and symptoms and 
facilitating completion of detoxification/extending treatment retention in subjects undergoing 
detoxification from short-acting opioids in a double-blind inpatient setting (Days 1-7) 
followed by an open-label inpatient/outpatient setting (Days 8-14).
It is hypothesized that a daily dose of either 2.4 mg or 3.2 mg lofexidine will achieve greater 
efficacy than placebo with respect to overall symptom relief over the first 7 days of opioid 
withdrawal (primary endpoint) and will increase the likelihood of subjects completing 
Days 1-7 of treatment (secondary endpoint). Further, safety measures in the 2.4 mg and 
3.2 mg total daily dose groups will be compared descriptively to assess whether the lower 
dose results in fewer and less severe adverse events than does the higher dose.
8 
STUDYSPONSOR
This study will be conducted under an Investigational New Drug (IND) application (#47,857) 
held by US WorldMeds, LLC.
9 STUDY SITES AND INVESTIGATORS
This study will be conducted at approximately 12 study sites in the US. In the event that the 
enrollment rate is unsatisfactory, additional centers will be added for a total site base of up to 
20. It is the responsibility of the Site Investigators to make sure this protocol is conducted in 
full conformance with the ethical principles detailed in Section 16 of this protocol. All data 
will be collected at the study sites on source documents and entered at the site into electronic 
case report forms (eCRFs) as described in Section 18.1 of this protocol.
10 INVESTIGATIONAL PLAN
10.1 Overall Design
This is a Phase 3, two-part, multicenter study to evaluate the dose-response, efficacy, and 
safety of lofexidine in alleviation of symptoms in subjects undergoing total and abrupt 
withdrawal from short-acting opioids. Any subject dependent on short-acting opioids (the 
primary projected indication for lofexidine) about to undergo opioid withdrawal will be 
eligible. Subjects will be evaluated for their compliance with protocol inclusion/exclusion 
criteria during a screening period, lasting up to 7 days.
The first part of the study will use an inpatient, randomized, double-blind, and placebo-
controlled design (Days 1-7) followed by a second part, an open-label, continuation treatment 
(Days 8-14). A total of 600 subjects will be randomized to receive lofexidine 2.4 mg total 
daily dose (0.6 mg QID), lofexidine 3.2 mg total daily dose (0.8 mg QID), or matching 
placebo in a 3:3:2 ratio (225:225:150) for 7 days (i.e., during the most intense stage of 
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withdrawal).  During the second part of the study (Days 8-14), all subjects, regardless of their 
treatment assignment (which will remain double-blinded), who successfully meet the 
definition for “completer” based on Days 1-7 (i.e., receives at least one dose of study 
medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop assessment on 
Day 7), will be eligible to receive open-label, variable dose lofexidine treatment (as 
determined by the Site Investigator, but not to exceed 3.2 mg/day) for up to an additional 
7 days in either an inpatient or outpatient setting depending on the wishes of the investigator 
and the subject. No subject will receive lofexidine for more than 14 days total from the onset 
of abstinence. There will be no initial dose run-up and no mandated terminal dose taper. 
Efficacy and safety assessments will be made daily (see detailed Schedule of Assessments in 
Table 1 of Section 15). Qualitative urine drug screening will be done every other day to 
monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
10.2 Number of Subjects
A sufficient number of subjects will be screened to randomize 600 subjects (225 in each 
lofexidine group and 150 in the placebo group) at approximately 12 study sites in the US
(should the enrollment rate be unsatisfactory, additional centers will be added for a total site 
base of up to 20).  The total number of subjects randomized at each site will depend on 
subject availability and will likely not be evenly distributed across all sites.
10.3 Duration of Study
The maximum duration of participation for each subject in this study will be 21 days, 
including the Screening/Baseline period, which can last up to 7 days, followed by up to 
14 days of treatment with study medication (lofexidine and/or placebo).
During Inpatient Treatment (Days 1-7), randomized subjects will receive lofexidine 2.4 mg 
total daily dose (0.6 QID), lofexidine 3.2 mg total daily dose (0.8 QID), or matching placebo 
treatment for up to 7 days. For Days 8-14, subjects will receive open-label, variable dose 
lofexidine for up to 7 additional days (open-label, continuation treatment). Full 
randomization into the study is anticipated to take 12 to 15 months to achieve (3-4 subjects 
per month per site), with the total clinical duration of the study anticipated to be 15 to 
18 months.
11 SELECTION OF STUDY POPULATION
11.1 Population Base
Any opioid-dependent subject about to undergo withdrawal from short-acting opioids will be 
evaluated for study eligibility after providing written informed consent. Entry into this study 
is open to both men and women and to all racial and ethnic subgroups.  An attempt will be 
made to include at least 25% female subjects and a mix of ethnicities reflecting the 
distribution in the local geographic regions of the study sites. Subjects will be recruited from 
a variety of sources, including subjects seeking treatment for opioid dependence via referrals 
from local treatment providers, word of mouth among subjects themselves also seeking 
treatment, and advertising in the local media. Recruitment advertisements will be approved 
by each site’s Institutional Review Board (IRB).
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Potential subjects may be accepted for screening after the nature and purpose of the 
investigation have been explained to them and after they have voluntarily given written 
informed consent (see Section 16.4).
11.2 Study Entrance Requirements
11.2.1 
Inclusion Criteria
To be eligible for participation, subjects must meet all of the following criteria:
1. Be male or female at least 18 years of age.
2. Have current dependence, according to the Mini International Neuropsychiatric
Interview (M.I.N.I.) [17, 18], on any opioid with a half-life similar to heroin or
morphine, including Vicodin®, Lortab®, Lorcet®, Percocet®, Percodan®, Tylox®,
or Hydrocodone (by any route of administration), or oxycodone (oxycodone and
oxycodone time-released formulation when crushed and snorted, injected or
swallowed after chewing).
3. Be seeking treatment for opioid dependence.
4. Have a score ≥2 on the Objective Opiate Withdrawal Scale (OOWS–Handelsman)
at Baseline.
5. Have reported use of heroin, morphine, or any opioid with a half-life similar to heroin
or morphine for at least 21 of the past 30 days.
6. Urine toxicology screen positive for opioids but negative for methadone and
buprenorphine.
7. If female and of childbearing potential, subject must agree to use of one of the
following methods of birth control:
x
oral contraceptives;
x
patch;
x
barrier (diaphragm, sponge or condom) plus spermicidal preparations;
x
intrauterine contraceptive system;
x
levonorgestrel implant;
x
medroxyprogesterone acetate contraceptive injection;
x
complete abstinence from sexual intercourse;
x
hormonal vaginal contraceptive ring; or
x
surgical sterilization or partner sterile (must have had documented proof).
8. Be able to verbalize understanding of the consent form, able to provide written
informed consent, verbalize willingness to complete study procedures, and pass the
study consent quiz with 100% accuracy (if necessary, quiz may be administered more
than one time).
11.2.2 
Exclusion Criteria
Subjects who meet any of the following criteria will not be allowed to participate:
1. Be a female subject who is pregnant or lactating.
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2. Have self-reported use of methadone or buprenorphine in the past 14 days.
3. Have serious medical illnesses including, but not limited to:
x
seizures, or those who have received anticonvulsant therapy during the past
5 years;
x
pancreatic disease such as insulin-dependent diabetes;
x
liver disease that requires medication or medical treatment, and/or aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 
5 times the upper limit of normal;
o
an infectious disease panel for hepatitis will be performed as an aid to
determine if the prospective subject has been exposed to a hepatitis virus;
positive hepatitis results do not exclude a prospective subject from
participation unless there is an indication of active liver disease;
x
gastrointestinal or renal disease, which would significantly impair absorption, 
metabolism or excretion of study drug, or would require medication or medical 
treatment.
4. Have a psychiatric disorder, based on the M.I.N.I., including but not limited to
dementia or any disorder that, in the opinion of the study physician requires ongoing
treatment that would make study participation unsafe or which would make treatment
compliance difficult.
5. Have self-reported acquired immune deficiency syndrome (AIDS) or self-reported
human immunodeficiency virus (HIV) positive status and taking retroviral
medications currently or within the past 4 weeks.
6. Abnormal cardiovascular exam at screening and before randomization, including any
of the following:
x
clinically significant abnormal electrocardiogram (ECG) (e.g., second or third
degree heart block, uncontrolled arrhythmia, or QTcF interval greater than 
450 msec for males and greater than 470 msec for females);
x
heart rate less than 55 bpm or symptomatic bradycardia;
x
systolic blood pressure (SBP) less than 95 mmHg or symptomatic hypotension;
x
diastolic blood pressure (DBP) less than 65 mmHg;
x
blood pressure (BP) greater than 155/95 mmHg; and
x
prior history of myocardial infarction.
7. Have clinically significant abnormal laboratory values.
8. Requiring any of the following medications currently or within the past 4 weeks:
psychotropics (including sedatives/hypnotics, antidepressants, neuroleptics),
prescription analgesics (excluding those listed in inclusion criterion #2 above),
anticonvulsants, antihypertensives, antiarrhythmics, antiretroviral, and cholesterol
lowering medications.  Nicotine replacement therapy (patch, inhaler, gum, or nasal
spray) will be allowed for nicotine-dependent subjects.
Note:  Use of a short-acting benzodiazepine (e.g., oxazepam) for insomnia during
Days 8-14 will not disqualify a subject.
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9. Current dependence (based on the M.I.N.I.) on any psychoactive substance (other
than that listed in inclusion criterion #2, caffeine or nicotine) that requires
detoxification.
10. Have donated blood within the last 8 weeks.
11. Have participated in an investigational drug study within the past 3 months.
12. Have such “poor” veins that even a single venipuncture cannot be obtained during
screening.
13. Have active tuberculosis (positive tuberculin test and/or confirmatory diagnostic
chest x-ray).
14. Have active syphilis.
Notes on inclusion/exclusion criterion: Potential subjects who are positive for syphilis (as 
detailed in Section 15.5.4.2) will not be eligible for study participation and will be referred 
for appropriate follow-up and/or treatment, if required.
The infectious disease panel for hepatitis is performed as an aid to determine if the 
prospective subject has been exposed to a hepatitis virus. Positive hepatitis results do not 
exclude a prospective subject from participation unless there is an indication of active liver 
disease.
Tuberculin test (purified protein derivative [PPD]) and/or a chest x-ray will be performed on 
all subjects. A positive PPD result does not exclude a prospective subject from participation, 
but if diagnostic tests (e.g., chest x-ray) indicate that active disease is present, subjects will 
be excluded from participation.
If any tests are positive, the subject will be notified of the test results and referred for 
treatment.
11.3 Screening Failures
Screening failures are potential study subjects who provide informed consent and fail 
inclusion and/or exclusion criteria or for other reasons are not allowed to participate. A 
screening log for all subjects who are screened will be maintained. The screening log will 
uniquely identify each subject and report whether he or she passed or failed screening, and, if 
he or she did not pass, the reasons for the screening failure.
Subjects who fail screening for any reason cannot be rescreened for study participation at a 
later time.
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12 INVESTIGATIONAL AGENTS
12.1 Lofexidine Hydrochloride
Lofexidine hydrochloride is an D2-adrenergic agonist with mild to moderate antihypertensive 
actions. It has the empirical formula C11H13Cl3N2O representing a molecular weight of 
295.61. The structural formula is:
Lofexidine hydrochloride is a synthetic product and has the chemical designation of 2-[1-
(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride.  It is a white to 
off-white crystalline powder that is very soluble in water and ethanol.  It is lightly soluble in 
2-propanol and practically insoluble in ether.  Lofexidine hydrochloride melts at 
approximately 126-128°C.
Lofexidine will be supplied by the Sponsor (USWM) in peach colored tablets containing 
0.2 mg of active medication for oral administration.
Lofexidine should be stored at room temperature in a secure area.
12.2 Placebo
Placebo will be supplied by the Sponsor (USWM) as an exact match of lofexidine, less the 
active ingredient.
12.3 Dispensing Investigational Agents
All investigational agents will be distributed from 
 (the pharmacy 
coordinating center) in “Subject Kits.”
For the Inpatient Treatment part of the study (Days 1-7), a supply of unassigned subject kits 
will be maintained at each participating site.  Each subject kit will contain 7 blister cards 
(packaged by 
 with the appropriate dosing of lofexidine and/or matched 
placebo for each day of the inpatient phase of the study.
For Days 8-14 (open-label treatment), lofexidine tablets will be supplied in uniquely-
identified 80-count bottles, which will be dispensed by the study pharmacist as determined 
clinically appropriate by the Site Investigator to the subject in individual prescription bottles.
One to 2 days of medication may be dispensed at each daily clinic visit to accommodate 
flexible scheduling (e.g., day and a half worth of medication to supply subject from one 
morning to the next afternoon depending on availability for clinic visit). The site will 
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maintain a dispensing log for each bottle and document the number of tablets dispensed to 
each subject along with the number of tablets returned, if any, by the subject at each 
outpatient visit.  Returned tablets will not be re-dispensed to future subjects.
All study medications will be dispensed by the site pharmacist or designee to the Site 
Investigators or their designee.
12.4 Blinding Plan
The subjects, Site Investigators, site personnel, Sponsor (USWM), and clinical personnel at 
the CRO (
 including the biostatistician will be blinded to 
medication assignment groups.  The study pharmacist at the central pharmacy (
 
) and bioanalytical personnel at the CRO will not be blinded to medication 
assignment.  The bioanalytical personnel will not be blinded because they will need to 
identify finger-prick pharmacokinetic samples from placebo subjects; these samples will not 
be analyzed.
The investigational agents, lofexidine (2.4 mg or 3.2 mg) and placebo, will be packaged in 
blister cards of matched appearance and labeling for the Inpatient Treatment part of the study 
(Days 1-7). Days 8-14 will be open-label, although subjects’ treatment assignment during 
Days 1-7 will remain blinded. Refer to Section 14.3.5 should breaking the blind become 
necessary for the safety of the subject.
12.5 Labeling
The investigational agents, lofexidine and placebo, will be packaged in blister cards for the 
Inpatient Treatment part of the study (Days 1-7) and further packaged in an outer carton 
(blister card kit).  Lofexidine will be packaged in bottles for Days 8-14 (open-label 
treatment).
The blister card kit (outer carton) will be labeled with the following information:
x
kit number
x
space for site personnel to enter subject’s number,
x
space for site personnel to enter subject initials/name code,
x
sponsor’s name,
x
protocol number,
x
number of tablets (per card and total for kit),
x
name/address of the pharmacy coordinating center 
 
x
24-hour emergency telephone number, and
x
the following statement – “Caution: New Drug – Limited by Federal Law to 
Investigational Use.”
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The individual blister card labels will include the following information:
x
kit number,
x
space for site personnel to enter subject’s number,
x
space for site personnel to enter subject initials/ name code,
x
sponsor’s name,
x
protocol number,
x
study day (e.g., Day 1, Day 2) and each row of tablets will be delineated with dosing 
times (i.e., 8AM, 1PM, 6PM, 11PM) to ensure that the appropriate tablets are given at 
each protocol-specified dosing time, and
x
a description of the investigational product:  “Lofexidine HCl 2.4 mg, Lofexidine HCl 
3.2 mg, or Placebo,” thus identifying the drug but preserving the blind.
The bottle product label will include the following information:
x
sponsor’s name,
x
protocol number,
x
a unique bottle number for purposes of investigational product accountability, and
x
a description of the investigational product, i.e., “Lofexidine HCl 0.2 mg tablets” as 
the portion of the study that will use bottled study drug under open-label conditions.
In the open-label phase of the study (Days 8-14), sites may dispense 1 to 2 days of 
medication at each daily clinic visit to accommodate flexible scheduling for use in an 
outpatient setting (e.g., day and a half worth of medication to supply subject from one 
morning to the next afternoon depending on availability for clinic visit).  In such cases, the 
redispensing container will include a subject label, supplied by the study site, and will 
include the following information:
x
sponsor’s name,
x
protocol number,
x
subject initials,
x
subject number,
x
study physician’s name,
x
site emergency contact telephone number,
x
description of the medication (i.e., “Lofexidine HCl 0.2 mg tablets”), 
x
number of tablets dispensed, and
x
directions for use.
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12.6 Storage
Investigational agents will be stored at room temperature in a secure location at the 
dispensing pharmacy or site.
12.7 Record of Administration
Accurate recording of all investigational agents received, dispensed, administered, and 
returned will be maintained by study site personnel.
12.8 Used/Unused Supplies
Unused investigational agents will be retained at the participating sites to enable a full 
investigational drug inventory by the sites’ respective monitor. If any investigational agent is 
lost or damaged, its disposition should be documented. The Sponsor will provide 
instructions to return the unused study drug to the pharmacy coordinating center periodically 
throughout the study (following monitor review) or at the end of the study for proper 
destruction in accordance with local and federal regulations.
12.9 Contraindications
To avoid drug-drug interactions, lofexidine should not be administered concurrently with:
x
tricyclic antidepressants – may reduce the efficacy of imidazoline derivatives;
x
alcohol, sedatives, and anaesthetics – may interact with lofexidine and enhance its central 
sedative effects; and
x
beta-receptor blockers – the combination of lofexidine and beta-receptor blockers should 
be used with caution to avoid the risk of excessive bradycardia.
13 TREATMENT PLAN
13.1 Investigational Agents
On Day 1 of the Inpatient Treatment part of the study, subjects will be randomized to one of 
two dose levels of lofexidine or placebo and receive the following daily treatment regimens 
through Day 7: lofexidine 2.4 mg/day (administered as 3 x 0.2 mg tablets and 1 placebo 
tablet QID), lofexidine 3.2 mg/day (administered as 4 x 0.2 mg tablets QID), or matching 
placebo (administered as 4 x placebo tablets QID). In order to maintain the treatment blind, 
all subjects will receive a total of 16 tablets per day whether active, placebo, or in 
combination to achieve the assigned dose.  Tablets will be provided in subject-specific kits, 
containing 7 blister cards (one for each study day).  Each blister card will contain 4 rows of 
4 tablets each, appropriately marked to indicate which row of tablets should be administered 
at each of the specified dosing times (8 AM, 1 PM, 6 PM, and 11 PM).  Dose kits for subjects 
randomized to lofexidine 3.2 mg/day will contain full blister cards of active tablets.  Dose 
kits for subjects randomized to lofexidine 2.4 mg/day will contain blister cards in which each 
dose row contains 3 active tablets and 1 placebo tablet.  Dose kits for subjects randomized to 
placebo will contain full blister cards of placebo tablets.
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For the Open-Label, Continuation Treatment part of the study (Days 8-14), subjects will 
receive lofexidine at variable dose, as determined by the Site Investigator (see Section 13.2).
13.2 Dose Administration
13.2.1 
Administration of Doses
During Inpatient Treatment (Days 1-7), subjects must take study medication orally, within a 
30-minute window, 15 minutes before or after 8 AM, 1 PM, 6 PM, and 11 PM.  The actual
date and time of each dose will be recorded in the subject’s source document and on the
eCRF.  Placebo will appear identical to lofexidine. Vital signs (blood pressure and pulse
[sitting or recumbent and standing], respiration, and temperature) will be measured before
each dose and 3.5 hours after each dose (with the exception of the dose taken at 11 PM,
where the measurement at 3.5 hours post-dose will not be done).  Details for obtaining vital
sign are provided in Section 15.5.2.
During Open-Label, Continuation Treatment (Days 8-14), there will be no mandated 
lofexidine dose regimen and subjects may receive lofexidine treatment during this time in 
either an inpatient or outpatient setting depending on the wishes of the Site Investigator and 
the subject. The rationale for the decision to continue treatment or not and the Site 
Investigator’s decision to continue treatment through either an inpatient or outpatient setting 
must be documented in the subject’s source document. The dose regimen will be determined 
by the Site Investigators as clinically indicated for relief of subjects’ symptoms, with 
supporting rationale for any dose changes recorded in the subject’s source document.  In no 
case is the dose of lofexidine to exceed 3.2 mg/day (or a single dose of 0.8 mg).  Previous 
studies have shown that dose titration is not necessary to reach a maximum intended dose.  
Also, abrupt withdrawal of lofexidine has not been found to have any significant safety 
issues.  Nevertheless, a dose taper may be appropriate given the dissipating severity of 
symptoms in the later days of withdrawal.  Vital signs (blood pressure and pulse [sitting or 
recumbent and standing]) should be assessed for one dose every day at pre-dose and 3.5 
hours post-dose on Days 8-13, with vital signs measured once pre-dose on Day 14.
As further guidance, the dosing regimen recommended for lofexidine (BritLofex™) in the 
UK is as follows:
“The dosage of lofexidine should be titrated according to the patient’s response.  Initial 
dosage should be 0.8 mg per day in divided doses.  The dosage may be increased by 
increments of 0.4 to 0.8 mg per day up to a maximum of 2.4 mg daily.  Maximum single 
dose should not exceed 4 x 0.2 mg tablets (0.8 mg).  Each patient should be assessed on an 
individual basis; those undergoing acute detoxification will usually require the highest 
recommend dose and dosage increments to provide optimum relief at the time of expected 
peak withdrawal symptoms.”
The lower maximum dose allowed in the UK (2.4 mg/day) may be reflective of the less 
severe opioid dependence experienced by patients in the UK. US studies have shown that 
3.2 mg/day can be safely administered (see Sections 6.3 and 6.4).
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Note:  In order to prevent dehydration from opioid withdrawal, increased fluid intake will be 
encouraged from the beginning of the study.  Instances in which study medication is not 
administered within the 30-minute windows as noted above will be documented as protocol 
deviations.
13.2.2 
Dose-Hold Criteria
Study medication will be held if pre-dose vital signs meet any of the following criteria: 
Resting (sitting or recumbent, if required, for treatment of an adverse event)
x
Systolic blood pressure <90 mmHg and >20% below screen value;
x
Diastolic blood pressure <50 mmHg and >20% below screen value;
x
Heart rate <50 bpm and >20% below screen value; and
x
Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness, 
syncope).
Orthostatic (after standing for 3 minutes)
x
Systolic blood pressure diastolic blood pressure, or pulse >25% below 
recumbent values.
All instances of dose-holds must be clearly documented in the subject’s source document.
13.2.3 
Discontinuation Criteria
A subject will be discontinued from the study if any of the following criteria are met:
x
Systolic blood pressure <70 mmHg and >20% below screen value;
x
Diastolic blood pressure <40 mmHg and >20% below screen value;
x
Heart rate <40 bpm and >20% below screen value;
x
QTcF >500 msec1 or >25% above screen value for both males and females;
x
Syncope;
x
Subject misses more than 2 doses in 24 hours during Days 1-7 prior to meeting 
"completer" criteria (i.e., receives at least one dose of study medication on Day 7 and 
completes the 3.5-hour post-dose SOWS-Gossop assessment on Day 7);
x
Subject misses more than a total of 6 doses during Days 1-7 prior to meeting 
“completer” criteria (i.e., receives at least one dose of study medication on Day 7 and 
completes the 3.5-hour post-dose SOWS-Gossop assessment on Day 7); and
x
Concomitant medication use (other than alumina, magnesia, and simethicone) for 
intolerable nausea and emesis.
1 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval. 
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Additional discontinuation criteria based on cardiovascular events are provided in 
Section 14.5.2.
13.3 Treatment Compliance
Each of the inpatient doses during Days 1-7 will be observed by the site staff.  Following 
administration of the oral study medication, hand and mouth checks will be performed to 
ensure that the dose is swallowed. In an inpatient setting during Days 8-14, each dose will be 
observed by study staff and hand and mouth checks will be performed.  In an outpatient 
setting during Days 8-14, self-dosing compliance will be evaluated by pill count and subject 
report at each clinic visit.  Subjects will be instructed to call the physician’s office before 
taking the next dose of study medication if they notice any marked dizziness, especially 
when standing from a sitting or lying position.  The physician will determine if the next dose 
should be delayed, skipped, or the subject should be seen.  Any change in physician-
prescribed dosing will be noted in the study file and confirmed also by pill count and subject 
report at the next visit.
13.4 Nicotine Replacement Therapy
Subjects may be permitted to smoke during their participation in the Inpatient Treatment part 
of the study (Days 1-7) based on individual site policy.  If they usually use tobacco products, 
the study physician will offer and encourage these subjects to use nicotine replacement 
therapy (patch, gum, inhaler, or nasal spray) while they are in the hospital to treat their 
nicotine withdrawal symptoms.  If smoking is permitted by a participating site, smoking 
breaks outside of the inpatient unit must be constantly observed and supervised.
The estimated total number of tobacco products used by subjects per day (Days 1-14) will be 
recorded in the subject’s source document and on the eCRF.
14 STUDY PROCEDURES
14.1 Subject Recruitment and Consent
Interested subjects, who respond to recruitment materials and are available to stay in the 
hospital or clinic for the 7-day Inpatient Treatment part of the study, will be scheduled to 
meet with a qualified investigative staff member and receive an explanation of the study 
purpose and requirements in lay language.  During the initial interview, the interviewer 
should not ask questions in a manner that reveals the eligibility criteria for study entry.
If still interested after receiving an explanation of the study, subjects will be given an 
opportunity to review, inquire about, and sign the study informed consent form (see Section 
16.4). The subject will then be given a copy of the signed consent form. After collecting 
demographic information (date of birth, gender, race, and ethnicity), site personnel will 
access the IWRS to obtain a unique subject number.  Subjects will proceed to the screening 
phase of the study.  Screening assessments must be completed within a 7-day time period, but 
can be completed as early as screening day 1, and randomization may be performed on the 
next calendar clinic visit day.  Subjects must be randomized no later than the 7th day of 
screening (Day 1). At no time during the screening process should individuals 
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be given information regarding inclusion or exclusion criteria, with the exception that 
subjects will be informed that they must exhibit signs of opioid withdrawal immediately 
before randomization into the study. When individuals are evaluated, questions should be 
asked in a way that the criteria are not discernible.
Any subject who has difficulty understanding the information contained in the consent form 
will reread the misunderstood portion(s) of the consent and discuss with a research staff 
member until s/he shows complete understanding of the information in the consent form, and 
may thus give full consent.  Subjects must complete a consent quiz with 100% accuracy 
before being randomized.  Research staff will work closely with the subject in an effort to 
help them understand the requirements of their participation. Subjects with literacy problems 
will be assisted to the extent possible.
Any subject who is unable to demonstrate understanding of the information contained in the 
informed consent will be excluded from study participation and assisted in finding other 
sources of treatment at the subject’s sole expense.  Subjects who are excluded, or who 
decline participation, may not be rescreened at a later time and will be given referrals to other 
resources in the area.  Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice.
14.2 Screening
Screening assessments will be conducted as shown in Table 1 (Section 15).  The screening 
period will last up to 7 days during which the subjects must satisfy the eligibility criteria and 
complete all required screening assessments.
14.3 Treatment Phase
14.3.1 
Baseline
After a potential participant has completed all screening assessments and has met all 
eligibility criteria to participate in the study, the Site Investigator or study coordinator will 
arrange for an early morning hospital or clinic study admission (Day 1).  The Baseline period 
is the morning of Day 1 after the subject has completed final eligibility testing 
(OOWS-Handelsman) and has been admitted to the inpatient study unit, but before 
randomization. Baseline assessments to be done are shown in Table 1 and explained in 
Section 15.2. Subjects admitted to the inpatient unit and successfully complete all Baseline 
measures will be randomized.  The Site Investigator or study coordinator will have the 
investigational agent dispensed and ready to administer, before the Day 1 8 AM dosing 
window.
14.3.2 
Subject Randomization
A prospective subject who meets all of the study inclusion criteria and does not meet any of 
the exclusion criteria may be randomized into the study. The final eligibility criterion is a 
score of at least 2 on the OOWS-Handelsman at Baseline.
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A stratified randomization procedure will be used to separately allocate male and female 
subjects in 1 of the 3 treatment groups: 2.4 mg lofexidine, 3.2 mg lofexidine, or placebo.  
Randomization will be implemented centrally, that is, take place across all investigational 
sites using an Interactive Web Response System (IWRS) managed by the CRO 
 
 Once eligibility criteria are confirmed at the Baseline visit, site personnel 
will access the IWRS and complete randomization procedures. The system will assign a 
unique kit number for drug dispensation according to the randomization scheme. The subject 
number assigned at screening should be used throughout the study in all source documents 
and eCRFs.
The Site Investigator or study coordinator will arrange for hospital or clinic admission (in the 
event that the subject was not admitted the night before randomization) of the subject and for 
investigational agent to be dispensed to initiate treatment.  Even if a subject does not actually 
receive any investigational agent after s/he has been randomized, s/he is considered to be in 
the intent-to-treat (ITT) population.  
 should be notified of any 
irregularities that occur during randomization.
14.3.3 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment)
After randomization, subjects will receive their first dose of study medication (lofexidine or 
placebo) during the 8 AM dosing window on Day 1.  Subjects will be dosed 4 times daily 
from Day 1 through Day 7 at 8 AM, 1 PM, 6 PM, and 11 PM.  Vital signs will be recorded 
within 30 minutes before every dose and 3.5 hours after the 8 AM, 1 PM, and 6 PM dose. 
Other clinical assessments will be gathered between 11:00 AM and noon each day.  These 
clinical assessments are described in detail in Sections 15.4 and 15.5.
14.3.4 
Days 8-14 (Open-Label, Continuation Treatment)
Subjects who successfully meet the definition for “completer” based on Days 1-7
(i.e., receives at least one dose of study medication on Day 7 and completes the 3.5-hour 
post-dose SOWS-Gossop assessment on Day 7) and if clinically indicated (as determined by 
the Site Investigator) may continue to receive lofexidine to control symptoms for up to an 
additional 7 days during Days 8-14. Subjects may be treated as inpatients or outpatients, 
depending on the wishes of the investigator and the subject, using open-label, variable dose 
lofexidine (as determined by the Site Investigator, but not to exceed 3.2 mg/day). The 
rationale for the decision to continue treatment or not and the Site Investigator’s decision to 
continue treatment through either an inpatient or outpatient setting must be documented in 
the subject’s source document and eCRF. Lofexidine treatment will terminate and the 
subject will be discontinued from the study when the Site Investigator judges that the acute 
phase of opioid withdrawal is essentially complete and the subject no longer needs treatment 
for abstinence.  In any event, no subject will continue to receive lofexidine treatment for 
more than 14 days total from the onset of abstinence. If being treated as an outpatient, the 
subject must return to the clinic daily for assessment (see a complete list of assessments in 
Table 1 of Section 15).
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14.3.5 
Maintaining and Breaking the Blind
In circumstances where breaking of the blind is necessary for subject safety, Investigators or 
emergent care professionals requesting to break the blind must call the Sponsor’s Medical 
Monitor (or designee) for consultation before unblinding unless immediate action is required.
The decision to break the study blind should be resorted to only in cases of life-threatening 
emergency when knowledge of the treatment arm investigational agent will influence clinical 
management.
Contact information for the Sponsor’s Medical Monitor is as follows:
If, after discussion with the Medical Monitor, it is determined that the study treatment should 
be disclosed, medical personnel will be able to access this information via IWRS.  
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 following information must be recorded in the subject’s record:  the reason for 
unblinding the code, the person who has unblinded the code, and the date and time of 
unblinding.
14.4 Subject Reimbursement
All compensation will be described in the informed consent form used by each site and 
approved by the site’s IRB or central IRB (
).
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14.5 Study Discontinuation
14.5.1 
Subject Discontinuation
A subject can withdraw his/her consent for participation in the study at any time without 
prejudice.  The Site Investigator may discontinue a subject if s/he deems it clinically 
appropriate for any reason. Additionally, the Site Investigator must discontinue a subject for 
any of the following reasons:
1. Cardiovascular events (see Section 14.5.2).
2. Serious medical problem thought to be related or unrelated to the study medications.
3. Intercurrent illness or medical complications that, in the opinion of the site investigator, 
preclude safe administration of study medications.
4. Evidence of illicit drug use while participating in the study during Days 1-7.
5. Alcohol or other sedative/hypnotic withdrawal signs and symptoms developing following 
enrollment into the study.
6. Requiring therapy with an exclusionary drug.
7. Lack of compliance with protocol and/or unit procedures.
8. During Days 1-7, missing more than 2 doses of study medication in a single 24-hour 
period or missing more than 6 doses of study medication prior to meeting “completer” 
criteria (i.e., receives at least one dose of study medication on Day 7 and completes the 
3.5-hour post-dose SOWS-Gossop assessment on Day 7). 
At any time after a subject meets “completer” criteria, they may be discontinued by the 
Investigator if s/he feels that the subject has achieved the treatment goal of acute 
detoxification/ transition.  This judgment by the Site Investigator will be made and recorded 
daily in the subject’s source document and on the eCRF on Days 7 (after end of double-blind 
dosing but before initiating open label dosing) through 14.
Subjects who are removed from study treatment because of adverse events (AEs) or serious 
adverse (SAEs) will be followed until they are medically stabilized to the satisfaction of the 
attending physician (see Sections 15.5.1, 16.7, and 16.8). Appropriate safety evaluations will 
continue to be collected until the subject is discharged from the treatment center or the 
maximum 14-day treatment period has expired.  This stabilization can include medically 
supervised opioid withdrawal (involving behavioral therapy, rescue opioid medications, 
and/or non-opioid pharmacotherapy) or referral to an appropriate methadone or 
buprenorphine therapy program.
Any subject that discontinues from the study, regardless of the reason, will be requested to 
complete all Study Discontinuation/End of Study assessments and procedures (see Table 1).
The reason for discontinuation will be recorded in the subject’s source document and on the 
end of study form provided in the subject’s eCRF.  Once discontinued, subjects may not re-
enter the study.  No randomized subject will be replaced.
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Study subjects discontinued from the protocol secondary to a medical or psychiatric concern 
deemed to be unrelated to lofexidine therapy will be referred, at the subject’s sole expense, 
for appropriate treatment, and may include psychological and lifestyle counseling, support 
groups, pharmacological, and medical treatment.  Subjects will be asked to sign a general 
consent for the release of information to the referred healthcare provider. Study staff may 
request transportation for emergency treatment of a subject if medically appropriate (e.g., for 
acutely psychotic or suicidal subjects).
14.5.2 
Cardiovascular Events Requiring Subject Discontinuation From Study
Subjects should be discontinued from the study for any of the reasons listed below, and the 
event should be recorded in the subject’s document and in the eCRF as an AE or SAE (see 
Sections 15.5.1, 16.7, and 16.8) and the subject followed until medically stabilized to the 
satisfaction of the attending physician.
1. New onset of clinically significant abnormal ECG (e.g., second or third degree heart
block or uncontrolled arrhythmia, prolonged QTcF interval2).
2. Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or
fluids).
3. Single occurrence of symptomatic bradycardia (as assessed by the Investigator,
regardless of blood pressure) associated with chest pain, shortness of breath, or decreased
level of consciousness.
4. Persistent hypertension – blood pressure ≥185/110 mmHg recorded on 3 separate 
occasions taken at least 5 minutes apart AND within a 1-hour time period.  If all 3
readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic ≥110 mmHg)
the subject must be terminated.
5. Medical Intervention for Cardiovascular Event:  Any medical intervention
(nonmedication or medication inclusive) used for the treatment of any cardiovascular
event, with the exception of a positional intervention in subjects displaying hypotension.
6. Any other clinically significant cardiovascular signs or symptoms that would place the
subject at risk.
14.5.3 
Trial Discontinuation
The Sponsor (USWM) has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following:
x
the incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects;
x
subject enrollment is unsatisfactory; and
x
data recording is inaccurate or incomplete.
2 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval.
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14.6 Concomitant Therapy
If the subject is admitted to the inpatient study unit the day before Baseline (i.e., Day -1), a 
single dose of a short-acting opioid (e.g., morphine) may be administered if needed to keep 
the subject reasonably comfortable; however, the administration may not occur after 8 PM on
Day -1.
The concomitant medications or therapies listed below are permitted during Days 1-7 and 
Days 8-14 of the study.
1. Multivitamins (≤1 tablet orally, administered daily at 9 AM).
2. Guaifenesin (for cough) (≤2 teaspoons orally every 2 hours, as needed [PRN]).
3. Alumina, Magnesia, and Simethicone (for emesis and nausea) (≤30 mL orally every
4 hours, PRN).
4. Dioctyl sodium sulfosuccinate (for constipation) (≤100 mg orally every 8 hours, PRN).
5. Psyllium hydrocolloid suspension (for constipation) (≤1 tablespoon orally every
12 hours, PRN).
6. Bismuth sulfate (Pepto-Bismol®) (for diarrhea) (≤6 doses of 30 mL orally every
24 hours, PRN).
7. Acetaminophen (for headache, muscle aches, or other discomfort) (≤4 doses of ≤650 mg
orally every 24 hours).
8. Zolpidem (for insomnia) (≤10 mg orally, PRN, may repeat 1 time if administered before
5:00 AM (i.e., 3 hours before the first morning dose of lofexidine or placebo).  Zolpidem
must not be administered before 11:00 PM (which is the time of the last daily dose of
lofexidine or placebo).
8a. Note:  A short-acting benzodiazepine (e.g., oxazepam) may be used ad libitum for
insomnia during the second part of the study (i.e., Days 8-14).
9. Nicotine replacement therapy (patch, inhaler, gum, nasal spray).
All other medications must be approved by the Sponsor’s Medical Monitor before 
administration.  If a subject requires any other medication for intolerable nausea and emesis 
(including a prescription opioid or non-opioid or an over-the-counter opioid or non-opioid) 
other than alumina, magnesia and simethicone, the subject will be discontinued from the 
study and given appropriate treatment according to the standard of care (see Section 14.5.1).
All medications taken will be recorded in the subject’s source document and eCRF along 
with dose, dates of administration, and reason for use.
Psychosocial therapy (e.g., art, music, group sessions) will be allowed per standard of care at 
individual study sites. Acupuncture, however, will not be allowed.  All therapies will be 
recorded in the subject’s source document and eCRF.
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15 CLINICAL EVALUATIONS
A detailed Schedule of Assessments to be done in the study is provided in Table 1.
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Table 1.
Schedule of Study Assessments
Randomized, Double-Blind, Placebo-Controlled (Days 1-7) followed by 
Open-Label, Continuation Treatment (Days 8-14)
Screening
Baseline
Inpatient Treatment
In/Outpatient Treatment
Study 
Discontinuation/
Activity
Days -6 to -1
Day 1
Days 1-7
Days 8-14
End of Study*
Informed Consent Signed
X
Screening Number Assigned
X
Inclusion/Exclusion Criteria
X
X (b)
Prior Medication History
X
X (b)
Demographics
X
Medical and Smoking History
X
Mini-International Neuropsychiatric Interview
X
Infectious Disease Assessments (c)
X
Pregnancy Test (d)
X
X
X
Height
X
Weight
X
X
Admission to Inpatient Unit
X
Randomization
X
Study Medication Administration
X (QID)
X (variable)
Medication Compliance
X
X
X
Discharge from Inpatient Unit
Day 7
Efficacy Assessments
Short Opiate Withdrawal Scale of Gossop (e)
X
X
X
X
Objective Opiate Withdrawal Scale of Handelsman (e)
X
X (f)
X
X
X
Modified Clinical Global Impression (e)
X
X
X
Visual Analog Scale for Efficacy (e)
X
X
X
Clinical Opiate Withdrawal Scale (e)
X
X
X
X
X
Concomitant Medications Assessment
X
X
X
Assessment of Detoxification Completion
X (g)
X
X
Safety Assessments
Adverse Events Assessment
X
X
X
Vital Signs (Sitting/Recumbent & Standing BP and pulse;
respiration, and temperature)
X
X
X (i)
X (j)
X
12-Lead Electrocardiogram (duplicate)
X (k)
X (l)
Day 8 and 14 (m)
X
Pharmacokinetic Sampling
X (n)
Pharmacokinetic Sampling
Day 3 and 6 (r)
Clinical Laboratory Tests (hematology, chemistry, urinalysis)
X
X (o)
X (o)
X
Physical Exam (p)
X
X
X
X
X
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Table 1.
Schedule of Study Assessments
Randomized, Double-Blind, Placebo-Controlled (Days 1-7) followed by 
Open-Label, Continuation Treatment (Days 8-14)
Screening
Baseline
Inpatient Treatment
In/Outpatient Treatment
Study 
Discontinuation/
Activity
Days -6 to -1
Day 1
Days 1-7
Days 8-14
End of Study*
C-SSRS Baseline Version
X
C-SSRS Since Last Visit Version
X (s)
X(t)
X
Urine Drug Screen (q)
X
X
X
X
X
Telephone Follow Up (h)
X
Abbreviations: BP = blood pressure; C-SSRS = Columbia Suicide Severity Scale;  QID = 4 times daily
*
The study discontinuation/end of study assessments/procedures should always be done upon exit from the study.
(a)
The Baseline period is the morning of admission, before randomization.
(b) This form is to be updated at Baseline.
(c)
A chest x-ray is required only if a PPD (purified protein derivative) skin test for tuberculosis is not done, the current PPD is positive, or if a past PPD was positive.
(d) The urine sample collected on the first day of screening will be divided into two aliquots.  One sample will be sent to the central lab (
) for
urinalysis and the other sample will be used for urine drug screening and immediate “dipstick” analysis of pregnancy (females only).
(e)
During Inpatient Treatment (Days 1-7), efficacy scales will be completed daily: the Short Opiate Withdrawal Scale of Gossop 3.5 hours (±10 minutes) after the first dose of study 
medication followed by the other efficacy scales shortly thereafter.  Efficacy scales will be completed daily before dosing during Days 8-14.
(f)
The Objective Opiate Withdrawal Scale of Handelsman (OOWS-Handelsman) will be completed at Baseline to determine final eligibility as subjects must have a score ≥2 in order 
to participate in the study (inclusion criterion #4).
(g) To be done at the end of double-blind dosing and before initiating open-label dosing.
(h) The follow-up telephone contact will be 30 days after the subject’s last dose and will include an evaluation of the subject’s current treatment status (e.g., relapse, current 
psychosocial treatment, successful entry into a methadone, buprenorphine, or naltrexone program) and an adverse event evaluation.
(i)
Vital signs (resting [sitting/recumbent] and standing blood pressure and pulse; respiration, and temperature) will be measured before every dose and 3.5 hours after study 
medication administration at 8 AM, 1 PM, and 6 PM (7 times per day).
(j)
Vital signs (resting [sitting/recumbent] and standing blood pressure, and pulse) will be measured at least once daily before dosing and 3.5 hours after dosing on Days 8-13 and once 
before any dose on Day 14. Oral temperature and respiration are not required measurements Days 8-14. Note that if subjects are being treated on an outpatient basis and cannot 
stay in the clinic for measurement of the 3.5-hour post-dose vital signs required on Days 8-13, they will be given a portable digital blood pressure machine for measurement of their 
vital signs at this required time point.  They will also be provided a diary to record the measurements.
(k) Baseline 12-lead electrocardiograms (ECGs) will be done on one day during the screening period, time-matched to the post randomization ECG schedule (i.e., pre-1 PM [before 
1 PM dose], 4 PM [3 hours post-dose], and 5 PM [4 hours post-dose]).
(l)
12-lead ECGs will be done before the first daily dose, pre-1 PM dose, at 4 PM, and at 5 PM on Days 1 and 7; and before the first daily dose only on Days 2 and 4..
(m) 12-lead ECGs will be done before the first daily dose and 3.5 hours after first daily dose on Day 8; on Day 14, the ECGs will be done before a dose on that day.
(n) A finger prick blood sample will be collected concurrently with each scheduled ECG during Days 1-7.
(o) Clinical lab testing will be done as clinically warranted throughout the study and at the end of double-blind dosing and before initiating open-label dosing.
(p) A complete physical examination will be performed during screening and the physical exam form will be updated at Baseline.  A complete physical examination will be performed 
on Day 1 (3-4 hours after randomization) and at the end of double-blind dosing and before initiating open-label dosing. During Days 8-14, a complete physical exam will be 
performed as clinically warranted and at discontinuation from the study.
(q) Urine drug screen will be done at least every other day to monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
(r)
A finger prick blood sample will be collected at 9 PM and 10 PM (3 and 4 hours, respectively, after the 6 PM dose).
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Table 1.
Schedule of Study Assessments
Randomized, Double-Blind, Placebo-Controlled (Days 1-7) followed by 
Open-Label, Continuation Treatment (Days 8-14)
Screening
Baseline
Inpatient Treatment
In/Outpatient Treatment
Study 
Discontinuation/
Activity
Days -6 to -1
Day 1
Days 1-7
Days 8-14
End of Study*
(s)
C-SSRS will completed at 3.5 hours after the first dose (8 AM) on Days 1-7.
(t)
C-SSRS will be completed once daily on Days 8-14.
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15.1 Screening Assessments
Subjects seeking treatment for opioid dependence at one of the study sites will be screened 
for study enrollment.  Screening assessments must be completed within a 7-day time period.  
Subjects cannot be admitted later than the morning of the 7th day of the screening period.  
Written informed consent must be obtained from all study subjects before initiation of any 
study procedures.
The following screening assessments must be completed during screening after written 
informed consent is obtained:  height; weight; vital signs; blood collection for standard 
clinical safety laboratory assessments (including hematology and biochemistry); urine 
sample for confirmatory drug testing, urinalysis, and pregnancy assessment (if female); and 
infectious disease assessment (see Section 15.5.4.2) and a chest x-ray if a past PPD skin test 
for tuberculosis was positive.
The urine sample collected will be divided into two aliquots.  One sample will go to the 
central lab (
 for urinalysis; the other sample will be used 
for “dipstick” analysis of pregnancy and qualitative drug screening.
The assessments listed below must also be performed during screening.
x
12-lead ECG (in duplicate) will be done on one day during the screening period,
time-matched to the post randomization ECG schedule, i.e., pre-1 PM (before 1 PM 
dose), 4 PM (3 hours post-dose), and 5 PM (4 hours post-dose).
x
Medical and smoking/alcohol history.
x
Complete physical examination.
x
Mini International Neuropsychiatric Interview (M.I.N.I.) [17, 18]. The M.I.N.I will 
be performed once at screening only to (1) establish that each potential subject is
opioid-dependent (inclusion criterion #2), (2) exclude other drug dependency 
(exclusion criterion #4), and (3) determine the absence of major psychiatric disorders 
(exclusion criterion #9).
x
Prior medications will be recorded to capture all medications taken in the past 
30 days.
x
OOWS-Handelsman.
x
Clinical Opiate Withdrawal Scale (COWS).
15.2 Baseline Assessments
The Baseline period is the morning of admission to the study, before randomization and 
dosing.  Prospective subjects who meet all eligibility criteria must be randomized to the study 
in time to give the first dose of study medication at 8 AM.
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The assessments listed below will be performed during the Baseline period.
x
OOWS-Handelsman (score must be ≥2 for randomization).
x
SOWS-Gossop.
x
COWS.
x
Vital signs (resting [sitting or recumbent, if applicable]) and standing blood pressure
and pulse; respiration, temperature) measurements.
x
Repeat pregnancy assessment (by “dipstick”), if female.
x
Repeat urine drug screen (by “dipstick”).
x
Update Inclusion/Exclusion Criteria form to reflect Baseline assessments.
x
Update prior medication form and physical examination form to capture any new 
medications and/or medical problems since screening.
x
Columbia Suicide Severity Rating Scale (C-SSRS) (Baseline version; Appendix 9).
15.3 Assessments During Treatment
15.3.1 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment)
The assessments listed below will be performed daily (unless otherwise specified) on 
Days 1-7 (see Section 15.3.3 for assessments/procedures required for early termination 
from the study).
x
Efficacy assessments at estimated time of maximum plasma concentration (Tmax,
i.e., 3.5 hours after the first daily dose) including:
¾ SOWS-Gossop;
¾ OOWS-Handelsman;
¾ Modified Clinical Global Impressions Scale (MCGI) (Subject and Rater);
¾ Visual Analog Scale for Efficacy (VAS-E); and
¾ COWS.
x
C-SSRS at 3.5 hours after the first dose (8 AM) on Days 1-7 (Since Last Visit
version; Appendix 10).
x
Concomitant medication assessment.
x
Completion of detoxification as assessed by the Site Investigator (after completion of 
the SOWS-Gossop and other efficacy scales) at the end of double-blind dosing and 
before initiating open-label dosing
x
Resting (sitting or recumbent, if applicable, for treatment of an adverse event) and 
standing blood pressure and pulse; respiration, and temperature before every dose and 
3.5 hours after the 8 AM, 1 PM, and 6 PM dose (7 times per day).
x
Continuous monitoring for AEs.
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x
12-lead ECGs (in duplicate) will be done before the first daily dose, pre-1 PM dose,
at 4 PM, and at 5 PM on Days 1 and 7; and before the first daily dose only on Days 2
and 4.
x
Complete physical examination 3 to 4 hours after randomization on Day 1 and at the 
end of double-blind dosing and before initiating open-label dosing.
x
Finger prick blood sample for pharmacokinetic (PK) analysis will be collected 
concurrently with each scheduled ECG during Days 1-7, and on Days 3 and 6 at 
3 and 4 hours post the 6 PM dose (9 PM and 10 PM). 
x
Clinical laboratory tests as clinically warranted and at the end of double-blind dosing 
and before initiating open-label dosing.
In addition, qualitative urine drug screening (by on-site use of “dipsticks”) will be done at 
least every other day to monitor for contraband.
15.3.2 
Days 8-14 (Open-Label, Continuation Treatment)
The assessments listed below will be performed daily (unless otherwise specified) on Days 
8-14 (see Section 15.3.3 for assessments/procedures required for discontinuation from the 
study).
x
Efficacy assessments before dosing including:
¾ SOWS-Gossop;
¾ OOWS-Handelsman;
¾ MCGI (Subject and Rater);
¾ VAS-E; and
¾ COWS.
x
C-SSRS before dosing (Since Last Visit version; Appendix 10).
x
Concomitant medication assessment.
x
Completion of detoxification as assessed by the Site Investigator.
x
Pill count to measure compliance with previous day’s doses.
x
Resting (sitting or recumbent, if required, for treatment of an AE) and standing blood 
pressure and pulse at least once daily before dosing and 3.5 hours after dosing on
Days 8-13 and once pre-dose Day 14. Note that if subjects are being treated on an 
outpatient basis and cannot stay in the clinic for measurement of the 3.5-hour post-
dose vital signs required on Days 8-13, they will be given a portable digital blood 
pressure machine for measurement of their vital signs at this required time point.  
They will also be provided a diary (Appendix 8) to record the measurements.
x
AE assessment.
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x
12-lead ECGs (in duplicate) will be done before the first daily dose and 3.5 hours 
after the first daily dose on Day 8.  On Day 14, 12-lead ECGs (in duplicate) will be 
done once before a dose on that day.
x
Clinical laboratory tests as clinically warranted.
x
Complete physical examination as clinically warranted.
Qualitative urine drug screening (by on-site use of “dipsticks”) will be done at least every 
other day to monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
15.3.3 
Study Discontinuation/End of Study
Any subject that discontinues from the study, regardless of the reason (see all scenarios listed 
in Section 14.5.1), will be requested to complete all Study Discontinuation/End of Study 
assessments and procedures as listed below after the last dose of study medication: 
x
Concomitant medication assessment.
x
Completion of detoxification as assessed by the Site Investigator.
x
Pill count to measure compliance with previous day’s doses if not already performed.
x
Blood pressure and pulse at rest (sitting or recumbent, if required, for treatment of 
an AE) and standing; respiration, and temperature.
x
AE assessment.
x
12-lead ECGs (in duplicate).
x
Clinical laboratory tests.
x
Complete physical examination (including body weight).
x
Pregnancy test.
x
Urine drug screen.
x
C-SSRS (Since Last Visit version; Appendix 10).
x
SOWS-Gossop.
x
OOWS-Handelsman.
x
MCGI (Subject and Rater).
x
VAS-E.
x
COWS.
A 30-day post discharge follow-up telephone contact will be made 30 days after the subject’s 
last dose for an adverse event evaluation and an evaluation of the subject’s current treatment 
status (e.g., relapse, current psychosocial treatment, successful entry into a methadone, 
buprenorphine, or naltrexone program).
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15.4 Efficacy Assessment Methods
15.4.1 
Short Opiate Withdrawal Scale (SOWS-Gossop)
The SOWS-Gossop [16] will be completed by the subject at baseline (before randomization), 
once daily at 3.5 hours (± 10 minutes) after the first dose of study medication on Days 1-7,
and once daily before dosing on Days 8-14. Note that at the time of each daily evaluation, 
subjects should consider their symptoms over the last 24-hour period or since the last time 
the subject took this test. Also, this scale should be completed before completion of the 
OOWS-Handelsman, MCGI, VAS-E, and COWS.
The SOWS-Gossop scale assesses subjective symptoms of opioid withdrawal (Appendix 1).
It is a subject-rated scale consisting of 10 items that are scored on a 4-point scale of 0 = none, 
1 = mild, 2 = moderate, and 3 = severe (minimum score of 0, maximum score of 30) (see 
Table 2 below).  The overall score will be the simple sum of the 10-item scores. Lower 
observed values in SOWS-Gossop scores indicate a more positive clinical outcome.
Table 2. 
SOWS-Gossop Scoring Method
Condition
Score
None
Mild
Moderate
Severe
Feeling Sick
0
1
2
3
Stomach Cramps
0
1
2
3
Muscle Spasms/Twitching
0
1
2
3
Feeling of Coldness
0
1
2
3
Heart Pounding
0
1
2
3
Muscular Tension
0
1
2
3
Aches and Pains
0
1
2
3
Yawning
0
1
2
3
Runny Eyes
0
1
2
3
Insomnia/Problems Sleeping
0
1
2
3
Note:  Possible score range = 0 to 30.
15.4.2 
Objective Opiate Withdrawal Scale (OOWS-Handelsman)
The OOWS-Handelsman [19] will be performed by a trained observer during screening, 
twice on Day 1 (during Baseline to confirm final eligibility for randomization [score of ≥2 is  
required per inclusion criterion #4] and 3.5 hours after the first dose of study medication, 
after completion of the SOWS-Gossop), once daily at 3.5 hours after the first dose of study 
medication on Days 2-7 (after completion of the SOWS-Gossop), and once daily before 
dosing on Days 8-14 (after completion of the SOWS-Gossop).
The subject will be observed for 5 minutes, and the presence or absence of 13 physical signs 
of opioid withdrawal will be recorded (Appendix 2). The presence of a sign will be assigned 
1 point, yielding a possible total score ranging from 0 to 13 (see Table 3 below). Lower 
observed values in OOWS-Handelsman scores indicate a more positive clinical outcome.
Ambient room temperature (should be 67-75°F) will be recorded on the eCRF for all OOWS-
Handelsman observations.
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Table 3. 
OOWS-Handelsman Scoring Method
Symptom (a)
Score (b)
0
1
Yawning( Frequency = # of yawns per observation period)
None
≥1
Rhinorrhea( Frequency = # of sniffs per observation period)
0-2
≥3
Piloerection (Gooseflesh - observe subject’s arm)
None
Present
Perspiration
None
Present
Lacrimation
None
Present
Mydriasis
None
Present
Tremors (hands)
None
Present
Hot and Cold Flashes (shivering or huddling for warmth)
None
Present
Restlessness (frequent shifts in position)
None
Present
Vomiting (c)
None
Any
Muscle Twitches
None
Any
Abdominal Cramps (holding stomach)
None
Present
Anxiety (d)
None
Mild, Moderate or Severe
(a) Observed over a 5-minute period.
(b) For total score: Minimum = 0; Maximum = 13.
(c) Present during 5-minute observation period.
(d) Mild = observable manifestations, such as foot shaking, fidgeting, finger tapping.
Moderate to severe = agitation, unable to sit, trembling, panicky, complains of difficulty in breathing, choking
sensations, palpitations.
15.4.3 
Modified Clinical Global Impressions Scale (MCGI)
The Clinical Global Impressions rating scale (1985) was developed by the National Institute 
of Mental Health (NIMH), and originally contained 3 questions.  For this study, Questions #1 
and #3 have been modified from the original scale, and Question #2 was not included
(Appendix 3).
In the original scale, Question #1 (severity of illness) evaluates the subject using a severity 
scale from 0 (not assessed), 1 (normal, not at all ill) to 7 (among the most extremely ill 
subjects).  The language of this question has been modified in this study for the subject 
assessment to make the scale more appropriate to opioid withdrawal.  The original 
Question #2 referred to “global improvement” and is omitted from this study, since all 
subjects will be treated, and there is no untreated screen withdrawal.  Question #3 (efficacy 
index) records responses on a factorial grid – side effects on one side and therapeutic effects 
on the other side.  Since there is no untreated screen withdrawal data, the therapeutic effect 
cannot be assessed; therefore, only the side effect responses will be examined.
The MCGI scale is used to estimate the overall clinical benefit of lofexidine treatment.  The 
MCGI will be completed once daily at 3.5 hours after the first dose of study medication on 
Days 1-7 (after completion of the SOWS-Gossop), and once daily before dosing on
Days 8-14 (after completion of the SOWS-Gossop). The modified subject and observer 
scales used in this study are presented below in Table 4. Lower observed values in MCGI 
scores indicate a more positive clinical outcome.
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Table 4.
MCGI Scoring Method
MCGI
Score
1
2
3
4
5
6
7
Subject Scale
Severity of Opiate 
Withdrawal
Symptoms (a)
None
Between 
none and 
mild
Mild
Moderate
Marked
Severe
Most 
severe I 
ever had
Side Effects (b)
None
Slight, does 
not 
significantly 
interfere with 
daily 
activities
Moderate, 
significantly 
interferes 
with daily 
activities
Severe, 
greater than 
symptom 
relief
Observer Scale
Severity of 
Illness (a)
Not at 
all ill
Borderline ill
Mildly ill
Moderately 
ill
Markedly 
ill
Severely 
ill
Among the 
most 
extremely 
ill subjects
Side Effects (b)
None
Does not 
significantly 
interfere with 
subject’s 
functioning
Significantly 
interferes 
with 
subject’s 
functioning
Out-weighs 
therapeutic 
effect
(a) Maximum score of 7.
(b) Maximum score of 4.
15.4.4 
Visual Analog Scale for Efficacy (VAS-E)
The effectiveness of lofexidine in alleviation of withdrawal sickness will be assessed by 
subjects using the VAS-E, which will be completed once daily on Days 1-7, 3.5 hours after 
the first dose of study medication (after completion of the SOWS-Gossop) and once daily 
before dosing on Days 8-14 (after completion of the SOWS-Gossop).  Subjects will make a 
mark on a 100-mm VAS scale to reflect the effectiveness of lofexidine in relieving 
withdrawal sickness from Not Effective at all (0 mm) to Completely Effective (100 mm).
Greater observed values in VAS-E scores indicate a more positive clinical outcome
(Appendix 4).
15.4.5 
Clinical Opiate Withdrawal Scale (COWS)
The COWS [20] will be used to assess the effectiveness of lofexidine in alleviation of opioid 
withdrawal, and will be completed during screening, at baseline (before randomization), once 
daily at 3.5 hours after the first dose of study medication on Days 1-7 (after completion of the 
SOWS-Gossop), and once daily before dosing on Days 8-14 (after completion of the 
SOWS-Gossop).  The COWS is a clinician-administered instrument that rates 11 common 
opioid withdrawal signs and symptoms (Appendix 5).  These include:  resting pulse rate; 
sweating; restlessness; pupil size; bone or joint aches; runny nose or tearing; gastrointestinal 
(GI) upset; tremor; yawning; anxiety or irritability; and gooseflesh skin.  The score for each 
item reflects the severity of the sign or symptom, and the total scores are grouped as mild 
(5-12 points), moderate (13-24 points), moderately severe (25-36 points), and severe (>36 
points).
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15.4.6 
Assessment of Completion of Detoxification
At the completion of Inpatient Treatment on Day 7 or, if applicable at early termination from 
Days 1-7, the Site Investigator will indicate if the subject has completed detoxification and 
can be discharged without further lofexidine treatment. The same assessment will be made at 
each visit during Days 8-14.
15.4.7 
Concomitant Medication Use
Multivitamins, nicotine replacement therapy, and several other concomitant medications for 
minor complaints (e.g., diarrhea, constipation, mild nausea, headache, muscle aches, cough, 
insomnia) will be allowed during the study.  All concomitant medications administered will 
be recorded daily.
15.4.8 
Withdrawal-Related Adverse Events
The Site Investigator will indicate, using his/her best judgment, whether any adverse event 
that occurs during the study is secondary to opioid withdrawal. Individual items reported on 
the efficacy scales (i.e., SOWS-Gossop, OOWS-Handelsman) do not automatically qualify as 
a withdrawal-related AE unless the subject specifically reports them in response to a non-
leading question (i.e., “How have you been feeling since I saw you last?”).  In the event a 
subject reports “withdrawal” or a similar event encompassing a collection of potential 
withdrawal symptoms, the subject should be asked to elaborate so that specific symptoms can 
be recorded on the AE eCRF. In this case, the AEs recorded should include both the original 
reported condition (e.g., “withdrawal syndrome”) as well as the individual symptoms that the 
subject lists after further inquiry (e.g., anxiety, upset stomach).
15.4.9 
Subject Treatment Status 30 Days After Last Dose
A follow-up telephone contact will be made 30 days after the subject’s last dose by the Site 
Investigator, including an evaluation of the subject’s current treatment status (e.g., relapse, 
current psychosocial treatment, successful entry into a methadone, buprenorphine, or 
naltrexone program) and an adverse event evaluation.
15.5 Safety Assessment Methods
15.5.1 
Adverse Events
Adverse events will be assessed and recorded around the same time each day by study staff 
during Days 1-7. If an AE requires medical attention, it should be reported to a study 
physician immediately.  A study physician must meet with the subject to assess all medical 
and psychiatric AEs reported by the subject, as well as those recorded by other study staff. 
Adverse events will be assessed by asking the subject, “How have you been feeling since I 
saw you last?” After current AEs are assessed, the study physician must review with the 
subject and assess any AEs unresolved from the previous day.  After each daily AE 
assessment, the physician will record in the subject’s source document and AE eCRF, 
according to the procedures described in Section 16.7, the type of AE and whether serious 
(SAE) or non-serious, severity of each AE, and the relationship to the study agent. These 
categories are asking for the physician’s best judgment of the severity and relatedness of 
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each AE. The physician will also record, based on his/her best judgment, whether the AE is 
secondary to opioid withdrawal (see Section 15.4.8).  In general, an AE should not be marked 
as withdrawal related AND related to study medication.
Any study subject with a related AE will be followed by the attending physician until the 
event is resolved to the satisfaction of the Site Investigator and Sponsor’s Medical Monitor.  
If the AE is unrelated, the subject will not be discharged until medically stable, and then will 
be referred, at the subject’s sole expense, for ongoing care and/or treatment, which may 
include psychological and lifestyle counseling, support groups, or pharmacological and 
medical treatment.
During Days 8-14, in either an inpatient or outpatient setting, subjects will be queried about 
adverse events daily.  All subjects will be instructed to contact the treating physician if he or 
she feels dizzy (especially on standing from a sitting or lying position) and delay additional 
lofexidine dosing until instructed by the physician.  All reported AEs will be recorded as 
described above.
15.5.2 
Vital Signs
Vital signs (systolic and diastolic blood pressure, pulse, respiration, temperature) are to be 
measured at screening for all subjects.
During Days 1-7, resting (sitting or recumbent, if required, for treatment of an adverse event) 
and standing systolic and diastolic blood pressure and pulse; respiration, and temperature will 
be measured at Baseline and on Days 1-7, within 30 minutes before receipt of study 
medication at 8 AM, 1 PM, 6 PM, and 11 PM and 3.5 hours (±15 minutes) after receipt of 
study medication at 8 AM, 1 PM, and 6 PM.
During open-label treatment, in an inpatient or outpatient setting, vital signs including resting 
(sitting or recumbent, if required, for treatment of an adverse event) and standing systolic and 
diastolic blood pressure and pulse will be measured at least once daily before dosing and 
3.5 hours (±30 minutes) after dosing on Days 8-13 and once before a dose on Day 14. If 
subjects are being treated on an outpatient basis and cannot stay in the clinic for 
measurement of the 3.5-hour post-dose vital signs required on Days 8-13, they will be given 
a portable digital blood pressure machine for measurement of their vital signs at this required 
time point.  They will also be provided a diary (Appendix 8) to record the measurements.
For the orthostatic blood pressure readings, subjects will remain at rest for 3 minutes before a 
blood pressure reading, and then stand for 3 minutes before a second blood pressure reading 
is taken. If a subject demonstrates potentially clinically significant vital signs, as per any one 
of the criteria (i.e., systolic values, diastolic values, or pulse values meet the specified 
criteria) in the guidelines shown below, the event should be recorded in the subject’s source 
document and eCRF as an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) and the subject 
should be followed until medically stabilized to the satisfaction of the attending physician. 
Additional dose-hold and discontinuation criteria are provided in Sections 13.2.2 and 13.2.3, 
respectively.
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Vital Sign 
Parameter
Observed 
Value
Change Relative
to Screen
Systolic Blood
≥180 mmHg
A
N
D
Increase of ≥20 mmHg
Pressure
≤90 mmHg
Decrease of ≥20 mmHg
Diastolic Blood
≥105 mmHg
Increase of ≥15 mmHg
Pressure
≤50 mmHg
Decrease of ≥15 mmHg
Pulse
≥120 bpm
Increase of ≥15 bpm
≤50 bpm
Decrease of ≥15 bpm
Operational Note: When a vital sign or QTcF reading meets any of the defined 
cut-off criteria for discontinuation, the values will be confirmed by repeating the 
measurement twice, approximately 10 to 15 minutes apart.  If 2 of the 3 total 
readings confirm that the subject meets discontinuation criteria, the subject will 
be terminated from the study.  If 2 of the 3 total readings are within acceptable 
limits (and they do not meet the other discontinuation criteria detailed in  
Section 14.5.2), the subject may continue in the study.
Additionally, when the subject is experiencing blood pressure- or pulse-related symptoms 
(e.g., lightheaded, dizziness, palpitations), these should be recorded in the subject’s source 
document and eCRF as an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) even if the vital 
signs values do not meet the predefined criteria shown above.
15.5.3 
12-Lead Electrocardiograms
Using ECG core lab-provided and validated instruments, baseline paper tracing 12-lead ECG 
(in duplicate) will be conducted on one day during the screening period, time-matched 
(± 15 minutes) to the post randomization ECG schedule, i.e., pre-1 PM (before 1 PM dose), 
4 PM (3 hours post-dose), and 5 PM (4 hours post-dose). During Days 1-7, 12-lead ECGs (in 
duplicate) will be conducted before the first daily dose, pre-1 PM dose, at 4 PM, and at 5 PM 
on Days 1 and 7; before the first daily dose only on Days 2 and 4; and, if applicable, early 
termination during Days 1-7. During open-label treatment, 12-lead ECGs (in duplicate) will 
be conducted as follows: before the first daily dose and 3.5 hours after the first daily dose on 
Day 8; once before a dose on Day 14; and, if applicable, at discontinuation from the study 
during Days 8-14. ECG intervals and abnormalities will be read centrally by a computer and 
confirmed by an individual accredited to read ECGs at the ECG core lab 
. A 
qualified physician on site will evaluate tracings if there is significant abnormality. The 
following intervals will be computed:
x
Ventricular Rate
Number of R waves appearing within a 6-second period, 
multiplied by 10;
x
PR Interval
Measured from the onset of the P wave to the onset of the QRS 
complex;
x
QRS Complex
Measured from the beginning of the down stroke of the Q wave 
to the completion of the upstroke of the S wave;
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x
QT Interval
x
QTc (Bazett)
x
QTc (Fridericia)
Measured from the beginning of the down stroke of the Q wave 
to the completion of the T wave;
QT interval corrected for heart rate using Bazett’s formula 
(QT/square root of RR) (for analysis purposes);
QT interval corrected for heart rate using Fridericia’s formula 
(QT/cube root of RR) (for safety monitoring/subject 
termination purposes).
At screening (baseline assessment), a QTcF interval greater 
than 450 msec for males and greater than 470 msec for females 
will exclude the subject from study participation (see exclusion 
criterion #6 in Section 11.2.2).  In such cases, 2 additional 
ECGs should be taken at 10- to 15-minute intervals.  The QTcF 
interval on all 3 ECGs should be confirmed by the Site 
Investigator and if 2 of the 3 QTcF intervals exceed the gender-
specific cut-off, then the subject should be judged a screen 
failure and not randomized to treatment.
During the treatment phase of the study, when any QTcF 
interval exceeds 495 msec, 2 additional ECGs should be taken 
at 10- to 15-minute intervals.  The QTcF interval on all 3 ECGs 
should be confirmed by the Site Investigator.  If it is 
determined that 2 of the 3 QTcF intervals exceed 500 msec or 
>25% above screen value, then the subject will be terminated
from the study.
Any time that 2 of the 3 QTcF measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor,
 
to discuss the subject and the 
AE/SAE determination.
15.5.4 
Clinical Laboratory Evaluations
15.5.4.1 
Standard Laboratory Tests
Standard clinical laboratory safety evaluations (see Table 5) will be performed for all 
subjects at screening, as needed at the physician’s discretion throughout the study, at the end 
of double-blind dosing and before initiating open-label dosing, and at discontinuation from 
the study. For this multicenter study, a central laboratory (
) 
will be used that is directly accredited by the College of American Pathologists (CAP) and 
licensed by the Clinical Laboratory Improvement Act of 1988 (CLIA); both certification and 
accreditation must be renewed every 2 years.  The laboratory will need to provide a copy of 
current certification and provide the normal values for all analytes to determine the upper 
limit of normal (ULN).
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Table 5. Hematology, Chemistry, and Urinalysis Tests
Hematology (a)
Chemistry (b)
Urinalysis
Hemoglobin
Cholesterol
Color
Hematocrit
Triglycerides
Clarity
Platelet count
Sodium
pH
Red blood cell (RBC) count
Potassium
Specific gravity
MCV
Chloride
Protein
MCH
Carbon dioxide (CO2)
Glucose
MCHC
Glucose
Ketones
RDW
Creatinine
Bilirubin
White blood cell (WBC) count
Albumin
Nitrite
WBC differential (% and Abs)
Total protein
Blood
neutrophils
Calcium
Urobilinogen
lymphocytes
Phosphorus
Leukocyte esterase
monocytes
Aspartate aminotransferase (AST)
WBC
eosinophils
Alanine aminotransferase (ALT)
RBC
basophils
Gamma-glutamyl transpeptidase (GGTP)
Epithelial cells
Prothrombin time (PT)
Total bilirubin
Bacteria
aPTT
Lactate dehydrogenase (LDH)
Mucus
Alkaline phosphatase
Casts
Blood urea nitrogen (BUN)
Crystals
Thyroid-stimulating hormone (TSH)
Free thyroxine (T4)
Abbreviations:  Abs = absolute; aPTT = activated partial thromboplastin time; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; MCHC = mean corpuscular hemoglobin concentration; 
RDW = red blood cell distribution width
(a) Blood will be collected in anticoagulant containing evacuated venous blood collection tubes 
(e.g., Vacutainer™).
(b) Blood will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures.
15.5.4.2 
Infectious Disease Panel and Syphilis Tests
The infectious disease panel and syphilis tests will be assayed at screening only.  Blood will 
be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures. Qualitative 
analysis reporting positive/negative results will be performed for the following analytes: 
Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B
core antibody (HBcAb), and Hepatitis C virus antibody (anti-HCV). A PPD skin test for 
tuberculosis and/or a chest x-ray will be performed on all subjects.  If the PPD is positive, a 
chest x-ray is required to assess active tuberculosis. If the subject reports that s/he has been 
previously positive for the PPD test, the PPD test will not be performed and only a chest 
x-ray will be required. Syphilis antibody testing will be performed using an automated 
enzyme immunoassay (EIA).  If the EIA is positive, a confirmatory rapid plasma reagin 
(RPR) test will be performed.  If the RPR test is non-reactive, a confirmatory TPPA 
(treponema pallidum particle agglutination assay) test will be performed.
If the PPD with chest x-ray, chest x-ray, or RPR/confirmatory TPPA test is positive, subjects 
will not be eligible for study participation and will be referred, at subject’s sole expense, for 
appropriate follow-up and/or treatment.
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15.5.4.3 
Urine Toxicology Screening
Qualitative urine drug screening (UDS) will be performed at screening for all subjects, at 
Baseline, and at least every other day for the following drugs:  amphetamines/
methamphetamines, cocaine, barbiturates, opiates, benzodiazepines, cannabinoids, 
methadone, and buprenorphine. The central lab will provide standard sets of UDS 
“dipsticks” for use across all sites.
15.5.4.4 
Pregnancy Test
A “dipstick” pregnancy test designed to measure human chorionic gonadotropin will be 
performed on the first day of screening, at Baseline, and at discontinuation from the study for 
all female subjects regardless of their childbearing capacity.  The central lab will provide 
study sites with a supply of pregnancy dipsticks.
15.5.4.5 
Pharmacokinetic Sampling
A finger prick blood sample will be collected concurrently with each scheduled ECG during 
Days 1-7 only. In addition, finger prick blood samples will be collected on Days 3 and 6 at 
9 PM and 10 PM (3 and 4 hours, respectively, after the 6 PM dose).
15.5.5 
Physical Examination
A complete physical examination of the oral cavity, head, eyes, ears, nose and throat, 
cardiovascular system, lungs, abdomen (liver/spleen), extremities, skin, neuropsychiatric 
mental status and sensory/motor status, musculoskeletal system, and general appearance 
should be performed at screening for all subjects.
An update of the Physical Exam is required at Baseline (before randomization on Day 1) and 
then a complete physical examination should be performed 3 to 4 hours after randomization 
on Day 1 and at the end of double-blind dosing and before initiating open-label dosing.  For 
Days 8-14, a complete physical examination should be performed as clinically warranted and 
at discontinuation from the study.
Height should be recorded at screening only.
15.5.6 
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS measures both suicidal ideation and suicidal behavior and will be completed at 
Baseline (before dosing on Day 1), 3.5 hours after the first dose (8 AM) on Days 1-7, and 
once daily pre-dose on Days 8-14 or, if applicable, at discontinuation from the study.  The 
Baseline version of the C-SSRS (Appendix 9) will be used to assess lifetime suicidality on
Day 1 (before dosing).  At all other protocol-specified time points, the C-SSRS – Since Last 
Visit version (Appendix 10) will be used to assess the subject’s suicidality since the last 
assessment.
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15.6 Other Assessments
15.6.1 
Prior Medications
All medications taken by the subject for the 30 days before screening and during the 
screening period will be recorded in the subject’s source document and on the Prior 
Medication eCRF.  Prior medication usage should be updated at Baseline.  The reported 
medications will be reviewed and approved by the Site Investigator/study physician for entry 
into the study.
15.6.2 
Concomitant Medication Administration
Concomitant medication administration will be recorded daily. All concomitant medications 
should be recorded in the subject’s source document and on the Concomitant Medication 
eCRF.  All medications taken by the subject during study participation that are not on the list 
of permitted concomitant medications (see Section 14.6) must be pre-approved by the Site 
Investigator/study physician with concurrence of the Sponsor’s Medical Monitor and 
recorded on the concomitant medication administration form.
16 REGULATORY AND REPORTING REQUIREMENTS
16.1 Good Clinical Practices
This study will be conducted in accordance with the most current version of the International 
Conference on Harmonization (ICH) Guideline for Good Clinical Practices (GCP).  An 
Operations Manual will be provided to all investigational sites as a study quality assurance 
tool.  The monitoring of the sites participating in the trial will be executed according to GCP 
guidelines.  Monitors will examine subjects’ study files including source documents in both 
the clinic files and subjects’ official medical records, and will also review 
regulatory/essential documents such as correspondence with the IRB and the Sponsor
(USWM).  Areas of particular concern will be subject informed consent issues, protocol 
adherence, safety monitoring, IRB reviews and approvals, safety reports/regulatory forms, 
subject records, study drug accountability, and principal investigator supervision and 
involvement in the trial.  Reports will be prepared following each visit and forwarded to the 
Sponsor’s Clinical Project Manager.  Monitors will also prepare follow-up letters detailing 
their findings and any items requiring further resolution or attention by the site.  Follow-up 
letters will be provided to the Site Investigator, site coordinator, and Sponsor’s Clinical 
Project Manager.
16.2 FDA Form 1572 and Financial Disclosure
The Site Investigator will sign a Statement of Investigator (FDA Form 1572) before initiating 
this study. The names of any sub-investigators must appear on this form.
The Site Investigator and any sub-investigators will also sign a Financial Disclosure form 
before initiating this study.
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16.3 Institutional Review Board Approval
Before initiating the study, Site Investigator will obtain written IRB approval to conduct the 
study.  No study medication will be shipped until IRB approval is obtained.  Should changes 
to the study protocol become necessary, protocol amendments (provided by the Sponsor) will 
be submitted in writing to the central IRB 
 and the Site Investigator’s IRB for IRB 
approval before implementation. In addition, IRBs will approve all advertising materials 
used for subject recruitment and any educational materials given to the subject. Annual 
reports and progress reports will be submitted to the IRB annually or at a frequency 
requested by the IRB.
The IRB must be a properly constituted board or committee operating in accordance with 
GCP Title 21 Part 56 of the US CFR relating to IRBs and the ICH Guideline for GCP (E6).
16.4 Informed Consent/HIPAA Authorization
Properly executed written informed consent, in compliance with 21 CFR 50 and ICH 
guidelines, shall be obtained from each subject before entering the subject into the trial.  
Attention is directed to the basic elements that are required in the informed consent under 
US Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]).  Additional 
elements of informed consent, if appropriate, must be included in the informed consent 
document (21 CFR 50.25[b]). A standard Informed Consent document will be approved by a 
central IRB
  Any study site that requires a site-specific Informed Consent document 
must have the document IRB-approved and the final IRB-approved document must be 
provided to the Sponsor for regulatory purposes.
All potential subjects for the study will be given a current copy of the Informed Consent 
Form to read.  The Site Investigator, sub-investigators, or study physician at each site will 
explain all aspects of the study in lay language and answer all of the subject’s questions 
regarding the study.  If the subject desires to participate in the study, s/he will be asked to 
sign the Informed Consent.  Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.  No subject will undergo any study 
procedures before signing the Informed Consent form, which should be signed before 
screening.  A signed copy will be given to the subject and a signed copy shall be maintained 
in the subject’s clinical file as well as the Regulatory Binder at each study site.  Subjects who 
refuse to participate or who withdraw from the study will be treated without prejudice.
Each subject must also sign a HIPAA (US Health Insurance Portability and Accountability 
Act) form before his/her participation in the study.  A signed copy must be provided to the 
subject and a signed copy shall be maintained in the subject’s clinical file.
16.5 Drug Accountability
All study drug required for completion of this study will be provided by the Sponsor 
(USWM).  Upon receipt, the investigator/pharmacist is responsible for taking inventory of
the investigational agents.  A record of this inventory must be kept and usage must be 
documented.  Any unused or expired investigational agent shall be returned to the Sponsor.
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16.6 Outside Monitoring
16.6.1 
Data and Safety Monitoring Board (DSMB)
Adverse event data reported during the study will be reviewed by a Data and Safety 
Monitoring Board (DSMB) comprised of outside experts in substance abuse treatment, 
clinical trials, and biostatistics.  The DSMB will meet by conference call or WebEx every 
3 months during the life of the study to review adverse event and serious adverse data tables 
and data listings.  Any serious adverse event requiring expedited reporting to the FDA will be 
reviewed immediately by the DSMB.  The board will be blinded to subjects’ actual treatment 
assignments, but may break the blind if safety concerns arise from the blinded data.  
Although the DSMB may also have access to efficacy data, it will not be commissioned to 
recommend trial termination due to superior treatment efficacy versus placebo, and the trial 
will not be stopped prematurely for that reason.
16.6.2 
Medical Monitor
The Sponsor’s (USWM) Medical Monitor will be responsible for attempting to establish 
concurrence with the Site Investigator on the severity and seriousness of any AEs and SAEs, 
the relatedness to the study treatments, the expectedness of the event, and for determining if 
the SAE should be reported to the FDA in a 7- or 15-day expedited report or an annual report 
(Appendix 6).  The Sponsor’s Medical Monitor will also be responsible for tracking and 
assessing trends in the SAEs reported. Further, the Medical Monitor is available to consult 
with the Site Investigators and coordinators on any medical issues related to the study 
(e.g., admission criteria, concomitant medications).
16.6.3 
Clinical Monitors
All Investigators will allow the Sponsor or its representatives to periodically audit, at 
mutually convenient times during and after the study, all eCRFs and corresponding source 
documents for each subject. These monitoring visits will provide an opportunity for 
evaluation of the progress of the study and to inform the Sponsor of potential problems.
The study will be monitored according to an approved monitoring plan.  The monitors will 
assure that submitted data are accurate and in agreement with source documentation; verify 
that investigational agents are properly stored and accounted for; verify that subjects’ consent 
for study participation has been properly obtained and documented; confirm that research 
subjects entered into the study meet inclusion and exclusion criteria; and assure that all 
essential documentation required by GCP guidelines are appropriately filed.
Monitors will conduct a site initiation visit before the start of the study for any 
investigational site not represented at the investigator meeting.  At this visit, the monitor will 
assure that proper study-related documentation exists, assist in training investigators and 
other site personnel in study procedures and GCP guidelines, confirm receipt of study 
supplies, and assure that acceptable facilities are available to conduct the study.
Routine monitoring visits by USWM or designee will be scheduled at appropriate intervals 
but more frequently at the beginning of the study. At these visits, the monitors will verify 
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that study procedures are being conducted according to the protocol guidelines and review 
AEs and SAEs. At the end of the study, they will advise on storage of study records and 
return of unused study agents. All sites should anticipate visits by the Sponsor, its 
representatives, and the FDA.
16.7 Adverse Event Reporting
In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the Site Investigator or sub-
investigators according to the specific instructions detailed in this section of the protocol and 
Appendix 6.  The occurrence of AEs will be assessed starting at the treatment phase of the 
protocol.
An AE is defined as any reaction, side effect, or untoward event that occurs during the course 
of the clinical trial, whether or not the event is considered related to the investigational agent 
or clinically significant.  For this study, events reported by the subject, as well as clinically 
significant abnormal findings in the opinion of the Investigator on physical examination, 
laboratory evaluation, or C-SSRS (for example, score of 3 or more on the scale) will be 
considered an AE and will be recorded in the subject’s source document and on the AE 
eCRF.  A new illness, symptom, sign or clinically significant clinical laboratory abnormality 
or worsening of a pre-existing condition or abnormality is considered an AE.  Stable chronic 
conditions, such as arthritis, which are present before clinical trial entry and do not worsen 
are not considered AEs.
After each AE assessment, the physician will record in the subject’s source document and on 
the AE eCRF the type of AE and whether serious (SAE) or non-serious, severity of each AE, 
and the relationship to the study agent. These categories are asking for the physician’s best 
judgment of the severity and relatedness of each AE.  The physician will also record, based 
on his/her best judgment, whether the AE is secondary to opioid withdrawal (see 
Section 15.4.8).  In general, an AE should not be marked as withdrawal related AND related 
to study medication.
Each day, a study physician must review any AEs that are reported as beginning or as 
continuing.  All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed by a study physician until satisfactory 
resolution.
16.8 Serious Adverse Events (SAEs)
Each adverse event or reaction will be classified by the Site Investigator as serious or 
non-serious. Based on the seriousness of the adverse event or reaction, appropriate reporting 
procedures will be followed.
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The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH-E2A March 1995, as implemented by the US FDA, defines a SAE or serious adverse 
drug experience as any untoward medical occurrence at any dose that:
x
results in death during the period of protocol-defined surveillance;
x
is life-threatening;
x
requires inpatient hospitalization or prolongation of existing hospitalization;
x
results in persistent or significant disability or incapacity; or
x
results in a congenital anomaly/birth defect.
Important medical events that may not result in death, be life–threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, the
event may jeopardize the subject and might require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.
An unexpected event is one that is not described with respect to nature, severity, or frequency 
in the product package insert or Investigator’s Brochure.
All subjects with SAEs must be followed up for outcome. If a study subject withdraws from 
the study or if an investigator decides to discontinue the subject from the study because of a
SAE, the subject must have appropriate follow-up medical monitoring including, if 
necessary, hospitalization.
Reporting requirements for SAEs are described in detail in Appendix 6. There can be serious 
consequences including ultimately, criminal and/or civil penalties for sponsors who fail to 
comply with FDA regulations governing the reporting of SAEs to the FDA. Any SAEs, 
including death due to any cause, which occurs to any subject entered into treatment in this 
study or within 30 days following cessation of the last dose of treatment with the study 
medication, whether or not considered related to the investigational product, must be reported 
within 24 hours, from the time any study staff member is made aware of such, to the Sponsor 
(USWM).
16.8.1 
Clarification of Serious Adverse Events
x
Death is an outcome of an AE, and not an AE in itself.  In reports of death due to 
“Disease Progression,” where no other information is provided, the death will be 
assumed to have resulted from progression of the disease being treated with the study 
treatment(s).
x
All deaths, regardless of cause or relationship, must be reported for subjects on study 
and for deaths occurring within 30 days of last study treatment or within 30 days of 
last study evaluation, whichever is longer.
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x
“Occurring at any dose” does not imply that the subject is receiving study treatment at 
the time of the event.  Dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE; however, administration of study drug may 
have contributed to the event.
x
“Life-threatening” means that the subject was at immediate risk of death from the 
event as it occurred.  This does not include an event that might have led to death if it 
had occurred with greater severity.
x
Complications that occur during hospitalizations are AEs.  If a complication prolongs 
the hospitalization, it is a SAE.
x
“In-patient hospitalization” means the subject has been formally admitted to a 
hospital for medical reasons, for any length of time.  This may or may not be
overnight.  It does not include presentation and care within an emergency department.
x
The Investigator should attempt to establish a diagnosis of the event on the basis of 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis 
should be documented as the AE and/or SAE and not the individual signs/symptoms.
A distinction should be drawn between seriousness and severity of AEs.  An AE that is 
assessed as severe should not be confused with a SAE.  Severity is a category used for rating 
the intensity of an event, and both AEs and SAEs can be assessed as severe (see Appendix 6 
for assessment of the intensity of an AE).  An event is defined as "serious" when it meets one 
of the predefined outcomes described above.
16.9 Overdose
Any accidental or intentional overdose (any increase in frequency or dosage of study 
treatment [lofexidine] that exceeds total dosing of 3.2 mg per day), misuse or abuse of study 
treatment, whether suspected or confirmed, and whether or not associated with an adverse 
experience, must be reported within 24 hours to USWM or designee. This will include 
providing details of signs or symptoms, clinical management, and outcome if available.
Any clinical sequelae in association with the overdose should be reported as an AE as 
outlined in Section 16.7 or SAE as outlined in Section 16.8.  An overdose will be considered 
a SAE only if any of the seriousness criteria are met in Section 16.8.
16.10 Pregnancy
Although pregnancy is not considered an AE, it is the responsibility of the Site Investigator 
or his or her designee to report any pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs during the study or within 
30 days of completing the study medication.  All subjects who become pregnant must be 
withdrawn from study medication and must be followed to the completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of infant) must also be 
reported to the Sponsor.
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17 STATISTICAL APPROACH
17.1 General Considerations
Continuous or ordered categorical variables not subject to censoring will be summarized with 
the mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and 
maximum. Continuous or ordered categorical variables subject to censoring (e.g., time to 
removal from study treatment) will be summarized by the 25th percentile, median, 75th
percentile derived from Kaplan-Meier estimates of probabilities. Unordered categorical 
variables will be summarized with counts and percentages. Descriptive statistics will be 
provided for each treatment group separately as well as all subjects combined. Additionally, 
descriptive statistics will be provided by gender.
Detailed methodology for the summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be prepared as a 
standalone document and finalized before database lock and unblinding of treatment 
assignments.
17.2 Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment)
It is hypothesized that a daily dose of either 2.4 mg or 3.2 mg lofexidine will achieve greater 
efficacy than placebo with respect to overall symptom relief over the first 7 days of opioid 
withdrawal (primary endpoint) and will increase the likelihood of subjects completing 
Days 1-7 of treatment (secondary endpoint). Further, safety measures in the 2.4 mg and 
3.2 mg total daily dose groups will be compared descriptively to assess whether the lower 
dose results in fewer and less severe adverse events than does the higher dose.
17.2.1 
Analysis Populations
Three principal analysis populations are defined as follows:
x
Intent-to-treat (ITT), consisting of all randomized subjects.  Subjects will be assigned 
for analysis according to the group to which they are randomized.
x
Modified intent-to-treat (mITT), consisting of all subjects in the ITT group who 
received at least one dose of study medication.
x
Safety consisting of all subjects who received at least one dose of study medication.
The principal analysis population for the analyses of demographics and baseline 
characteristics and efficacy will be the mITT population. Sensitivity analyses of the 
completion status endpoint will be carried out on the ITT population. Safety summaries will 
be provided for the Safety population. Data recorded on subjects who are in the ITT but not 
in the mITT or Safety populations will be included in data listings.
17.2.2 
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively.
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17.2.3 
Subject Disposition
Subject disposition will be summarized descriptively.
17.2.4 
Primary Efficacy Endpoint 
The primary efficacy endpoint is:
x
AUC based on SOWS-Gossop scores from Days 1 through 7.
17.2.5 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is:
x
Completion status (i.e., whether a subject receives at least one dose of study 
medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7).
17.2.6 
Tertiary/Exploratory Endpoints 
The tertiary/exploratory endpoints are:
x
SOWS-Gossop, OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and 
COWS scores on Days 1, 2, 3, 4, 5, 6, and 7;
x
Retention analysis (time to removal from study treatment) over the 7 inpatient days;
x
Concomitant medication analysis;
x
Withdrawal-related AE analysis; 
x
Evaluation of subject treatment status 30 days after last dose;
x
Status of detoxification on Day 7 or early termination as assessed by the 
Site Investigator; and
x
In addition, single items (e.g., sweating, anxiety) from the OOWS-Handelsman and 
COWS that are not included in the SOWS-Gossop may be analyzed, as may AUC
based on COWS scores from Days 1 through 7.
17.2.7 
Control of the False Positive Rate and Statistical Testing Strategy
All statistical tests for efficacy will be one-sided. For the primary and secondary endpoints,
the treatment comparisons subject to control of the false positive rate will be 3.2 mg 
lofexidine vs. placebo and 2.4 mg lofexidine vs. placebo. (Comparisons of 3.2 mg vs. 2.4 mg 
will be descriptive.) The familywise error rate (FWE) for the collection of primary and 
secondary endpoint comparisons will be controlled at the 0.025 level, one-sided, by a 
sequential testing strategy in which hypotheses are tested in the following order, each at the 
0.025 level, one-sided.
1. Primary: AUC(1-7), 3.2 mg lofexidine versus placebo;
2. Primary: AUC(1-7), 2.4 mg lofexidine versus placebo;
3. Secondary: Completion rate, 3.2 mg lofexidine versus placebo; and
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4. Secondary: Completion rate, 2.4 mg lofexidine versus placebo.
Adjusted p-values for these 4 treatment comparisons, based on this sequence of statistical 
tests, are defined in the table below.
Test 
Order
Endpoint Comparison
P-value
Unadjusted (a)
Adjusted
1
AUC(1-7), 3.2 mg vs placebo
p1
p1
2
AUC(1-7), 2.4 mg vs placebo
p2
max(p1, p2)
3
Completion rate, 3.2 mg vs placebo
p3
max(p1, p2, p3)
4
Completion rate, 2.4 mg vs placebo
p4
max(p1, p2, p3, p4)
(a) P-values p1 and p2 are one-sided, derived from the statistical test described in Section 17.2.8.1;
p-values p3 and p4 are one-sided, derived from the statistical test described in Section 17.2.8.2. 
Any adjusted p-value less than 0.025 in magnitude will be declared statistically significant.
The tertiary/exploratory endpoints will be tested without multiplicity adjustment.
17.2.8 
Statistical Methods for Efficacy
17.2.8.1 
SOWS-Gossop AUC(1-7)
A pattern-mixture approach [21], with subjects stratified by disposition within Days 1-7, will 
be used in assessing SOWS-Gossop AUC(1-7). The 4 disposition strata are subjects: who 
complete Days 1-7 of the study (see Section 17.2.5); who discontinue due to lack of efficacy 
(including adverse events related to opioid withdrawal); who discontinue due to adverse 
events related to intolerability or toxicity to study drug; and who discontinue for other 
reasons. The inference is comprised of several steps:
1. Transformation. Because of the inherent skewness in the SOWS-Gossop scores the raw
data will first be transformed to the logarithm of the score plus 1.0.
2. Modeling. A linear mixed effects repeated-measures model will be constructed for the
SOWS-Gossop score. The fixed effects will be disposition stratum, treatment and time,
and their interactions, as well as a main effect of gender (randomization stratification
factor) and baseline SOWS-Gossop score as a one degree of freedom covariate.  For each
combination of treatment and stratum, the time course will be modeled as a linear change
point model, allowing for one slope between Days 1 and 2 and a possibly different slope
from Days 2 through 7. The model will parameterized to ensure that the predictions from
the two line segments agree at Day 2. Subjects will be treated as a random effect, and the
slope and intercept parameters will be treated as random coefficients.  Modeling the time
course, rather than using each time point as a discrete level of a model factor, allows
estimation of group means through Day 7 even in the non-completer strata. The choice
of Day 2 as the change point is based on prior lofexidine studies, in which SOWS-Gossop
mean scores in the placebo group increased from Day 1 to Day 2 and then decreased
through Day 7. The modeling allows a different time course for each of the lofexidine
dose groups.
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3. Point estimates of AUC(1-7). For each combination of disposition stratum, treatment
and study day, the estimated least squares means SOWS-Gossop (on the log scale) for
males and females will be combined using a weighted average, the weights being the
relative proportions of males and females in the mITT population. The results will then
be transformed back to the original SOWS-Gossop scale of measurement, from which
point estimates of AUC(1-7) for each combination of stratum and treatment will be
computed using the trapezoidal rule. It should be noted that these calculations will not be
derived from AUC(1-7) computed within individual subjects, many of whom will have
incomplete data for the later study days in Days 1-7. In particular, there will be no
imputation of data for individual subjects.
4. Estimates of treatment effect. For each active treatment, the treatment effect (lofexidine
3.2 mg versus placebo or lofexidine 2.4 mg versus placebo) will be estimated with
respect to AUC(1-7) within each disposition stratum. Then a weighted average of
treatment effects will be computed, where the weights are the relative proportions of
subjects in the 4 strata.
5. Interval estimates of AUC(1-7) and hypothesis testing. The covariance matrix of the
mixed model’s estimated fixed effects will be used with standard linear model methods to
derive the covariance matrix of the weighted average of male and female log-transformed
SOWS-Gossop scores. The multivariate delta method will be used to derive the
covariance matrix of the back-transformed SOWS-Gossop time course. Standard linear
model methods will then be used to derive the covariance matrix of the weighted average
of AUC(1-7) treatment effects, from which confidence intervals and p-values will be
derived.
17.2.8.2 
Completion Status
The proportion of subjects in each treatment arm who receive at least one dose of study 
medication on Day 7 and complete the 3.5-hour post-dose SOWS-Gossop assessment on 
Day 7 will be analyzed using Cochran-Mantel-Haenszel tests, with gender as the stratifying 
factor. One test will compare the 3.2 mg lofexidine group to placebo; a second will compare 
the 2.4 mg lofexidine group to placebo.
17.2.8.3 
SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7
The pattern-mixture approach, with the same stratification and treatment of gender used for 
the AUC(1-7) analysis, will be used to assess treatment effect with respect to SOWS-Gossop 
on Days 1, 2, 3, 4, 5 and 6 (but not 7). A single linear mixed effects repeated-measures 
model will be constructed for the transformed SOWS-Gossop score. Subject will be a 
random effect. The fixed effects will be disposition stratum, treatment and time, with each 
study day as a discrete level of the time factor, and their interactions. Estimated means for 
each combination of stratum, treatment and day will be back-transformed to the original 
SOWS-Gossop scale of measurement. Like the AUC(1-7) calculation, the weighted average 
of treatment effects will be calculated along with confidence intervals and p-values. This 
approach will provide no information on the non-completer strata on Day 7. Therefore, the 
modeled time course from the AUC(1-7) analysis will be used to estimate SOWS-Gossop on 
Day 7 for all combinations of disposition stratum and treatment, and Day 7 comparisons will 
be based on these estimates.
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17.2.8.4 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS
The same methods used for SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7 will be used for 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS scores on Days 1, 2, 3, 
4, 5, 6, and 7. Types of data transformation, if any, to be used before mixed effects 
modeling, will be specified in the SAP.
17.2.8.5 
Retention Analysis (Time to Removal from Study Treatment)
Time to removal from study treatment is defined as the last study day on which the subject 
received treatment. The time for subjects who complete some but not all treatment on Day 7
will be Day 7, uncensored. Subjects who complete all treatments on Day 7 will be censored 
at Day 7. This endpoint will be summarized descriptively for each combination of treatment 
group and gender with Kaplan-Meier curves and tabulations of the number and percentage of 
subjects newly removed from receiving study treatment on each of inpatient Days 1 to 7.
Each lofexidine dose group will be compared inferentially to placebo with a Cox 
proportional hazards regression model of time to removal from study, stratified by gender, 
with treatment as the independent variable. The estimated hazards ratio will be reported as a 
descriptive measure. The p-value on the log hazards ratio will be converted to a one-tailed 
p-value by considering whether the hazard ratio indicates a delay in time to removal in the 
lofexidine group versus the placebo group.
17.2.8.6 
Concomitant Medication Analysis
For each of Days 1 to 7, each subject’s number of concomitant medication doses taken will 
be treated as a continuous variable. Descriptive statistics will be provided on the as-observed 
data on each study day.  In addition, least squares means and p-values comparing each 
treatment to placebo will be obtained with the same methods used for SOWS-Gossop on 
Days 1, 2, 3, 4, 5, 6, and 7. Types of data transformation, if any, to be used before mixed 
effects modeling, will be specified in the SAP.
17.2.8.7 
Status of Detoxification on Day 7 or Early Termination as Assessed by the 
Site Investigator
Descriptive statistics (numbers and percentages) on the status of detoxification 
(successful/unsuccessful) as assessed by the Site Investigator at Day 7 or early termination 
will be presented by treatment group overall and by gender within treatment group.
17.2.8.8 
Single Items from the OOWS-Handelsman and COWS, and COWS AUC(1-7)
Single items (e.g., sweating, anxiety) from the OOWS-Handelsman and COWS that are not 
included in the SOWS-Gossop may be analyzed; the scores will be treated as continuous 
variables and analyzed using the same methods used for SOWS-Gossop on Days 1, 2, 3, 4, 5, 
6, and 7. COWS AUC(1-7) may also be analyzed; a modeling approach analogous to the 
modeling of SOWS-Gossop AUC(1-7) will be used. While the functional form of the time 
course for SOWS-Gossop is based on historical data, the functional form of the time course 
for COWS will be based on the data from this study.
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17.2.9 
Power Calculations
Treatment effect and subject variability with respect to SOWS-Gossop scores were estimated 
from the prior Phase 3 study (USWM-LX1-3002), using the random coefficients model 
planned for the present study and estimating the treatment effect of 3.2 mg lofexidine versus 
placebo with respect to AUC(1-7). It was assumed that the treatment effect of the 2.4 mg 
lofexidine dose will be three-fourths the treatment effect of the 3.2 mg dose. The table below 
shows the power to find a significant treatment effect for the comparisons of the two 
lofexidine treatments versus placebo, assuming a sample size allocation ratio of 3:3:2 
(3.2 mg lofexidine : 2.4 mg lofexidine : placebo) and accounting for the sequential testing 
approach described in Section 17.2.7. The power to find a statistically significant effect of 
the 3.2 mg lofexidine dose with respect to AUC(1-7) is in excess of 90% with the planned 
total sample size of 600.
Power (%) with Respect to AUC(1-7)
Total 
Sample Size
3.2 mg Lofexidine
versus Placebo
2.4 mg Lofexidine 
versus Placebo
600
94.6
72.6
550
92.6
67.6
500
90.1
62.2
450
86.8
55.7
17.2.10 Subgroup Analyses
The models used for the primary analysis will be modified for each of several subgroups to 
include the subgroup and its interaction with treatment as a fixed effect.  Subgroups include 
age, gender, and race. The SAP will list all subgroups to be analyzed, their classifications 
(e.g., age dichotomization, race groupings), and modeling details.
17.2.11 Safety Measures
The safety measures during Days 1-7 of the study are AEs, vital signs, ECGs (primarily 
evaluated for changes in QTcF versus time-matched controls for both doses of lofexidine and 
placebo), clinical laboratory measures, physical exams, and suicidal ideation and behavior.
Adverse event summaries will include tabulations overall and by seriousness, severity, and 
causality assessment. The data from these measures recorded during Days 1-7 will be 
summarized descriptively by treatment group.  In addition, each lofexidine group will be 
compared inferentially to the placebo group using chi-square tests for categorical variables 
and t-tests within an analysis of variance for continuous variables; the resulting p-values will 
not be adjusted for multiple testing.
17.3 Days 8-14 (Open-Label, Continuation Treatment)
Safety and effectiveness endpoints for Days 8-14 will be summarized by randomized 
treatment group.
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17.3.1 
Assessment of Effectiveness
Summary statistics will be provided by treatment day (overall and by gender) for:
x
SOWS-Gossop;
x
OOWS-Handelsman;
x
MCGI (Subject and Rater);
x
VAS-E; and
x
COWS.
In addition, the following will be summarized overall and by gender over Days 8-14:
x
Duration of exposure;
x
Number and proportion of subjects successfully completing detoxification as assessed 
by the Site Investigator;
x
Distribution of number of days required to complete detoxification as assessed by the 
Site Investigator;
x
Average daily dose of lofexidine; and
x
Concomitant medications.
17.3.2 
Assessment of Safety
Safety measures will be summarized for the following subject cohorts:
x
All treated subjects;
x
Treated subjects without urinary evidence of illicit drug use; and
x
Treated subjects with urinary evidence of illicit drug use (may be further subdivided 
by type of illicit drug used).
Descriptive statistics will be provided for:
x
All AEs;
x
New onset AEs (including those observed during Days 1-7 whose severity during 
Days 8-14 is greater than observed during Days 1-7);
x
Vital signs;
x
ECGs;
x
Clinical laboratory tests;
x
Physical examinations; and
x
C-SSRS.
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18 DATA MANAGEMENT AND CASE REPORT FORMS (CRFS)
Data management activities and statistical analytical support will be coordinated through the 
CRO (
). The CRO will be responsible for the construction and 
accuracy of the study database.
18.1 Data Collection
Data will be collected at the study sites on source documents, which will be entered at the 
site into electronic CRFs (eCRFs). The eCRFs will be supplied by the CRO (
 
). CRFs are to be completed on an ongoing basis during the study. The 
medical chart and the source documents are the source of verification of data. CRFs should 
be completed according to the instructions in the study operations manual.
The Site Investigator is responsible for maintaining accurate, complete, and up-to-date 
records for each subject. The Site Investigator is also responsible for maintaining any source 
documentation related to the study, including any films, lab reports, or ECG tracings.
Data generated by this study must be available for inspection by representatives of the 
US FDA, the Sponsor (USWM), the Sponsor representatives, the central IRB 
 and 
the site’s IRB.
18.2 Electronic Data Capture
Data entered by site personnel into the electronic data capture (EDC) system will be 
reviewed by the CRO (
).  If incomplete or inaccurate data are 
found, a query in the EDC system will be generated for response by the clinical site. Sites 
will promptly resolve data inconsistencies and errors.  An audit trail of any corrections or 
changes to the data in the EDC system will be maintained.  USWM will receive reports at 
least monthly regarding the quality and quantity of data submitted to the CRO.
Site Investigators agree to routine data audits by the staff of USWM.  USWM monitors will 
routinely visit each site to assure that data entered in the EDC system are in agreement with 
source documents at the sites.  The monitors will also verify that investigational agents have 
been properly stored and accounted for, subject informed consent for study participation has 
been obtained and documented in the subject’s progress notes, all essential documents 
required by GCP regulations are on file, and sites are conducting the study according to the 
research protocol.
18.3 Data Analysis
When the study is completed, all data have been entered into the clinical database, and the 
final database has been locked, statistical analysis of the data will be performed by the 
CRO’s (
) statisticians or an independent statistician in accordance 
with the Analytical Plan of this protocol (see Section 17) and detailed in the SAP. 
Periodically, during the investigation, the CRO will also prepare summary reports of the data, 
with no identification or grouping by randomized treatment, so that progress of the study can 
be monitored.  Various reports will be prepared for USWM and others, as appropriate.
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18.4 Study Documentation and Records Retention
Study documentation includes all eCRFs, data correction forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence 
and regulatory documents (e.g., signed protocol and amendments, IRB correspondence and 
approved consent form and signed informed consent forms, Statement of Investigator form, 
and clinical supplies receipt and distribution records).
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. Accordingly, source documents include, but are not limited to, laboratory reports, 
ECG tracings, x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound 
photographs, subject progress notes, hospital charts or pharmacy records, and any other 
similar reports or records of any procedure performed in accordance with the protocol.  
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.  Any duplicate of a source document to be retained as a 
part of a eCRF should maintain subject confidentiality per HIPAA.
Government agency regulations and directives require that the investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. These documents must be 
kept for a minimum of 2 years after the approval of a new drug application (NDA) and 
finalization of all marketing strategies, or if the NDA is not approved, for 2 years after 
discontinuation of the IND, whichever is the later. In all instances sites must get permission 
from USWM before disposition of any study documentation and materials.
18.5 Confidentiality
18.5.1 
Confidentiality of Data
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom 
of Information Act providing, in part, that proprietary information furnished to clinical 
investigators and IRBs will be kept confidential by the FDA only if maintained in confidence 
by the Site Investigator and IRB.
By participating in this protocol the Site Investigator affirms to USWM that information 
furnished to the Site Investigator by USWM will be maintained in confidence and such 
information will be divulged to the IRB, Ethical Review Committee (or similar or expert 
committee), affiliated institution, and employees only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution, and employees.
18.5.2 
Confidentiality of Subject Records
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports, and other 
records will be coded using alpha-numeric identifiers only.  Only research and clinical 
records will be stored in a locked cabinet.  Only research staff and USWM officials will have 
access to the records.  Subject information will not be released without written permission, 
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except as necessary for monitoring by the FDA or USWM.  USWM will file for a Certificate 
of Confidentiality that will cover all sites participating in the study (see Appendix 7).
By participating in this protocol the investigator agrees that within local regulatory 
restrictions and ethical considerations, USWM or any regulatory agency may consult and/or 
copy study documents in order to verify eCRF data.
Subject confidentiality will be maintained in any publications or presentations that result 
from this study.
19 PUBLICATIONS OF THE STUDY RESULTS
It is understood by the Site Investigator that the information generated in this study will be 
used by the Sponsor (USWM) in connection with the development of the product and 
therefore may be disclosed to government agencies in various countries.  To allow for the use 
of information derived from the study, it is understood that the Site Investigator is obliged to 
provide the Sponsor with complete test results, all study data, and access to all study records.
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences.  
Because this is a multicenter study, the combined results of the study will be published 
before the Investigator submits site-specific results for publication.  Any results of medical 
investigations with the Sponsor’s products and/or publication/lecture/manuscripts based 
thereon, shall be exchanged and discussed by the Site Investigator and Sponsor 
representative(s) 60 days before submission for publication or presentation.  Due regard shall 
be given to the Sponsor’s legitimate interests, e.g., manuscript authorship, obtaining optimal 
patent protection, coordinating and maintaining the proprietary nature of submissions to 
health authorities, coordinating with other ongoing studies in the same field, and protecting 
confidential data and information.
The Sponsor shall be furnished with a copy of any proposed publication.  In cases of 
publications or presentations of material arising from multicenter clinical investigations, the 
Sponsor is to serve as coordinator and referee.  Individual investigators who are part of a 
multicenter investigation may not publish or present data that are considered common to a 
multicenter investigation without the consent of the other participating investigators and the 
prior review of the Sponsor.  In case of disagreement amongst the investigators participating 
in a multicenter investigation, the Sponsor will be the final arbiter.  Sponsor comments shall 
be given without undue delay, and not later than within 60 days.  If they are not accepted, the 
senior author of the manuscript and the Sponsor’s representatives shall promptly meet to 
discuss further and endeavor to agree on the final wording and/or disposition of the 
publication.  The above procedure also applies to studies that are not completed, including 
those that are prematurely discontinued.
Results from investigations shall not be made available to any third party by the investigating 
team outside the publication procedure as outlined previously.  The Sponsor will not quote 
from publications by investigators in its scientific information and/or promotional material 
without full acknowledgment of the source (i.e., author and reference).
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20 PROTOCOL ADHERENCE AND AMENDMENTS
The Site Investigator and each sub-investigator must adhere to the protocol as detailed in this 
document. Only the Sponsor (USWM) may modify the protocol.  All amendments that have 
an impact on subject risk or the study objectives, or require revision of the informed consent 
document, must receive approval from the DSMB and central IRB/individual site’s IRB 
before their implementation.
21 QUALITY CONTROL AND QUALITY ASSURANCE
Following written standard operating procedures, study monitors will verify that the clinical 
trial is conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  Reports on monitoring activities will 
be submitted to the Sponsor.
The Sponsor (USWM) will secure agreement from all involved parties to ensure direct access 
to all trial-related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by local and regulatory authorities.
The CRO (
will be the Data Coordinating Center and will 
implement quality control procedures in accordance with GCPs and their internal Standard 
Operating Procedures, beginning with the data entry system and generate data quality control 
checks that will be run on the database.  Any missing data or data anomalies will be 
communicated to the site for clarification and resolution.
22 REFERENCES
1.
Substance Abuse and Mental Health Services Administration (SAMHSA), Office of
Applied Studies (2008).  Results from the 2007 National Survey on Drug Use and
Health:  National Findings (NSDUH Series H-34, DHHS Publication No. SMA
08-4343).  Rockville, MD.  http://oas.samhsa.gov
2.
National Institutes of Health.  Fact Sheet-Heroin Addiction.  September 2006.
Bethesda, MD.
http://www.nih.gov/about/researchresultsforthepublic/HeroinAddiction.pdf
3.
Archibold RC.  In heartland death, traces of heroin’s spread.  New York Times.
May 30, 2009. http://www.nytimes.com/2009/05/31/us/31border.html
4.
The DAWN Report.  Trends in emergency department visits involving nonmedical use
of narcotic pain relievers.  June 18, 2010.
http://oas.samhsa.gov/2k10/dawn016/opioided.htm
5.
Methadone is a schedule II drug.  See 21 C.F.R. § 1308.12(c)(10) (isomethadone);
§ 1308.12(c)(15) (methadone); and § 1308.12(c)(16) (methadone-intermediate,
4-cyano-2-dimethylamino-4,4-diphenyl butane).  Buprenorphine is a schedule III drug.
See 21 C.F.R. § 1308.13(e)(2)(i).
6.
Gowing L, Farrell M, Ali R, White JM.  Alpha 2-adrenergic agonists for the
management of opioid withdrawal.  Cochrane Database Syst Rev 2008, Issue 4.
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7.
Kahn A, Mumford JP, Rogers GA, Beckford H.  Double-blind study of lofexidine and
clonidine in the detoxification of opiate addicts in hospital.  Drug Alcohol Depend
1997;44:57-61.
8.
Lin SK, Strang J, Su LW, Tsai CJ, Hu WH.  Double-blind randomized controlled trial
of lofexidine versus clonidine in the treatment of heroin withdrawal.  Drug Alcohol
Depend 1997;48:127-133.
9.
Carnwath T, Hardman J.  Randomised double-blind comparison of lofexidine and
clonidine in the out-patient treatment of opiate withdrawal.  Drug Alcohol Depend
1998;50:251-254.
10.
Gerra G, Zaimovica A, Giusti F, et al.  Lofexidine versus clonidine in rapid opiate
detoxification.  J Subst Abuse Treatment 2001;21:11-17.
11.
Yu E, Herman BH, Miotto K, et al.  In-patient safety evaluation of lofexidine (alpha-2
adrenergic agonist) for opiate detoxification.  Drug Alcohol Depend 2001;63: S175.
12.
Yu E, Miotto K, Akerele E, et al.  A phase 3 placebo-controlled, double blind, multi-
site trial of the α2-noradrenergic agonist, lofexidine, for opioid withdrawal.  Drug
Alcohol Depend 2008;97:158-168.
13.
Gorodetzky CW.  A phase III, randomized, multi-center, double blind, placebo
controlled study of safety and efficacy of lofexidine for relief of symptoms in subjects
undergoing inpatient opiate detoxification.  US WorldMeds Report for Protocol
USWM-LX1-3002, March 14, 2010.
14.
Heyman ER.  An open-label, single-dose, pilot study to determine the maximum
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and
women.  CardioCore Report 01496KM, April 27, 2010.
15.
Leibowitz MT.  An open-label, single-dose, pilot study to determine the maximum
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and
women.  CEDRA Report DCN 01496KM, April 22, 2010.
16.
Gossop M.  The development of a short opiate withdrawal scale (SOWS).  Addict
Behav 1990;15(5):487-490.
17.
Medical Outcomes Systems.  M.I.N.I. International Neuropsychiatric Interview
(M.I.N.I.), version 6.0 (10/10/10).  https://www.medical-outcomes.com/index/mini/.
08 March 2013.
18.
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al. The M.I.N.I. International
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured
diagnostic psychiatric interview. J Clin Psychiatry 1998;59(suppl 20):22-33.
19.
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD.  Two
new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse
1987;13(3):293-308.
20.
Wesson DR, Ling W.  The clinical opiate withdrawal scale (COWS).  J Psychoactive
Drugs 2003;35(2):253-259.
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21.
Little RJA.  Pattern-mixture models for multivariate incomplete data.  Journal of the
American Statistical Association 1993;88:125-134.
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March 12, 2013 
USWM-LX1-3003-1 Administrative Change #1 
To Whom It May Concern: 
US WorldMeds, LLC would like to notify you of a change being made in the protocol­
specified clinical trial material labeling requirements for protocol USWM-LX1-3003-1 
Protocol Amendment 1 dated 08-MAR-2013. 
The name of the study (ie, full protocol title), will not be included in final clinical trial 
material labeling. The Sponsor's name and the protocol number will be provided, in 
addition to the information as outlined in Section 12.5. 
US WorldMeds, LLC will notify all Site Investigators this change in protocol-specified 
labeling requirements, and the change will be incorporated into any future Protocol 
Amendments. 
Thank you, and please do not hesitate to contact me with any questions. 
Best regards, 
 
Clinical Operations Lead 
US WorldMeds, LLC 
4010 Dupont Circle, Suite L-07 •Louisville, KY 40207 • 502-714-7800 • www.usworldmeds.com 
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CLINICAL STUDY PROTOCOL
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety, and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine
Treatment (Days 8-14)
Protocol Number:
USWM-LX1-3003-1
Product:
Lofexidine
Investigational New Drug (IND) Number:
IND 47,857
Development Phase of Study:
Phase 3
Medical Monitor:
Contract Research Organization (CRO):
Sponsor:
US WorldMeds, LLC
4010 Dupont Circle, Ste L-07
Louisville, KY  40207
Protocol Date:
August 10, 2012
Amendment No. 01 Date:
March 8, 2013
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.
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1 PROTOCOL AMENDMENT SUMMARY
Changes made in this amendment to the protocol for Study USWM-LX1-3003-1 
(Amendment No. 1) and the rationale supporting these changes are listed below.
Location
Modification/Rationale
Title Page,
Synopsis
Protocol title was clarified to better reflect the 2-part design of the 
study.
Synopsis, 
11.2.1, 11.2.2
Inclusion criterion #2, exclusion criterion #4, and exclusion criterion #9
were modified to use the Mini International Neuropsychiatric Interview 
(M.I.N.I.) rather than the Structured Clinical Interview for DSM-IV-TR 
Axis I Disorders (SCID) to establish the appropriate dependence 
diagnosis on opioids, exclude other drug dependency, and determine the 
absence of major psychiatric disorders.  The M.I.N.I. is a validated 
scale (Sheehan et al., 1998) and is used commonly in clinical practice 
and research studies.
Synopsis
Number of study sites was updated from 10 to approximately 12.
Synopsis;
6.6; 14.3.4; 
17.2.5; 17.2.8.2
The definition of completion status was clarified to: whether a subject 
receives at least one dose of study medication on Day 7 and completes 
the 3.5-hour post-dose Short Opiate Withdrawal Scale of Gossop 
(SOWS-Gossop) assessment on Day 7.
Synopsis; 9; 
10.2
Text was added to allow additional study sites (up to 20) in the event 
that the enrollment rate is unsatisfactory.
Synopsis;
11.2.1
Inclusion criterion #8 was removed because completion of the 
Objective Opiate Withdrawal Scale of Handelsman (OOWS-
Handelsman) at baseline is covered in inclusion criterion #4.
Synopsis; 
11.2.2; 13.2.3; 
15.5.2; 15.5.3; 
17.2.11
Text was modified to use QTc (Fridericia) instead of QTc (Bazett) for 
safety monitoring/subject termination purposes because QTcF is now 
more commonly used when correcting for low pulse rates.
Synopsis; 
15.3.1; 15.3.2; 
15.4.5; 17.2.6;
17.2.8.4; 17.3.1
Clinical Opiate Withdrawal Scale (COWS) was added as an efficacy 
measure for consistency with efficacy measures evaluated in other 
lofexidine clinical trials.
Synopsis, 
17.2.6, 17.2.8.8
Text was added to allow for the potential analysis of single items 
(e.g., sweating, anxiety) from the OOWS-Handelsman and COWS that 
are not included in the SOWS-Gossop, as well as area under the curve 
(AUC) based on COWS scores from Days 1 through 7.
Synopsis; 
17.2.6; 17.2.8.7
Status of detoxification on Day 7 or early termination was added as a
tertiary/exploratory endpoint because these data are being collected.
Synopsis; 
17.3.1
The tertiary endpoint (Days 8-14) was clarified for number of days 
required to complete detoxification “as assessed by the Site 
Investigator.”
5
Abbreviation list was updated.
6.1
Text was updated for consistency with other more current documents.
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Location
Modification/Rationale
6.4
Text was updated to account for more current safety information.
10.1
Second paragraph was clarified regarding subject eligibility for 
treatment in the open-label part of the study.
12.4
First paragraph was clarified to indicate the biostatistician will be 
blinded to medication assignment groups and that the finger-prick 
pharmacokinetic samples from placebo subjects will not be analyzed.
The third and fourth paragraphs were removed.  A cross-reference to 
Section 14.3.5 was added, which details requirements should 
unblinding become necessary for the safety of the subject.
12.5
Text was clarified regarding labeling of investigational agents.
13.2.1
Second paragraph was clarified to require the Site Investigator’s 
rationale for his/her decision to continue subject’s treatment in either an 
inpatient or outpatient setting.
13.2.2
Dose-hold criteria was clarified for symptoms of hypotension and/or 
bradycardia and a statement was added regarding the need to record all 
instances of dose-holds in source documents.
14.3.2
Second paragraph was clarified to indicate randomization will be done 
using an Interactive Voice Response System (IVRS) or an Interactive 
Web Response System (IWRS) managed by the CRO.
14.3.5
First and last paragraphs were clarified regarding breaking the study 
blind.
14.5.1
First paragraph was clarified regarding when subjects “may” or “must” 
be terminated from the study. Also, Item 8 was clarified regarding 
termination requirements for missed doses.
14.5.2
Item 2 was clarified regarding termination requirements for persistent 
symptomatic hypotension, either not responding to bed rest or fluids.
15
Table 1 was modified to:
x Add SOWS-Gossop at baseline.
x Add COWS at screening, baseline, and each day during treatment 
(Days 1-7 and Days 8-14).
x Add OOWS-Handelsman at screening.
x Replace the SCID with the M.I.N.I.
x To allow subjects to record the 3.5-hour post-dose vital signs 
measurements using a portable digital blood pressure machine if they 
are being treated on an outpatient basis and cannot stay in the clinic 
for this required post-dose measurement (see footnote j).
15.1
Screening assessments were clarified to include alcohol history.
Text was revised to use the M.I.N.I. rather than SCID.
15.2
SOWS-Gossop was added as a required baseline assessment so it can be 
used as a covariate in the analysis.
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Location
Modification/Rationale
15.4.1
First paragraph was clarified to provide a window (± 10 minutes) for 
the 3.5-hour post first daily dose recording of the SOWS-Gossop.  Also, 
text was clarified to indicate that for each daily evaluation, subject’s 
should consider their symptoms over the last 24-hour period.
15.4.8;
Appendix 6
Text was clarified regarding what should be recorded as withdrawal-
related adverse events.
15.5.2
Second paragraph was clarified to provide a window (± 15 minutes) for 
the required 3.5-hour post-dose measurement of vital signs.
Third paragraph, which pertains to the open-label part of the study
(Days 8-14), was clarified to provide a window (± 30 minutes) for the 
required 3.5-hour post-dose measurement of vital signs.  Also, a 
provision was added to allow subjects to record the 3.5-hour post-dose 
measurements using a portable digital blood pressure machine if they 
are being treated on an outpatient basis and cannot stay in the clinic for 
this required post-dose measurement.
15.5.3
Text was clarified to provide a window (± 15 minutes) for the required 
ECG recordings.
15.5.3
Text was clarified that an on-site qualified physician (rather than a 
cardiologist) will evaluate ECG tracings if there is significant 
abnormality.
16.2
Title of subsection and text was clarified to remove reference to FDA 
Form 3454 because the Sponsor (US WorldMeds) will provide a 
Financial Disclosure form (internal template) to each site for signature.
16.6.1
Text was revised to reflect the use of the National Institute on Drug 
Abuse (NIDA) Data and Safety Monitoring Board (DSMB) for this 
study.
16.8.1
Section was added to further clarify SAE requirements.
16.9
Section was added for Overdose.
17.2.8.1
Statistical methods were revised to use 4 disposition strata in assessing 
SOWS-Gossop AUC(1-7). Also, Item 2 (Modeling) was revised to 
include baseline SOWS-Gossop score as a covariate in the analysis.
18.1; 18.4;
18.5.2
Text was clarified to indicate that all data will be entered electronically 
(eCRFs) and no paper CRFs will be used.
18.2
Text was clarified regarding electronic data capture requirements.
22
References were added for COWS (Wesson and Ling, 2003) and for the 
M.I.N.I. (Sheehan et al., 1998; Medical Outcomes Systems, M.I.N.I. 
version 6.0).
Appendices 1-5
Scales used to assess efficacy were added as appendices.
Appendix 6
Item E was clarified to indicate where SAEs are to be reported.
Appendix 8
Outpatient Vital Signs Diary was added so subjects who cannot stay in 
the clinic for the 3.5-hour post-dose vital signs measurement can 
complete this measurement using a portable digital blood pressure 
machine and record the results in the diary.
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Several administrative clarifications were also made to the protocol, with updates throughout 
as appropriate:
x
 as the central IRB;
x
 as the Clinical Research Organization (CRO);
x
 as the pharmacy coordinating center/central pharmacy;
x
as the central laboratory for analysis of blood and 
urine samples; and
x
 as the ECG core lab.
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2 SIGNATURE PAGE
By signing below, US WorldMeds, LLC and the investigator indicate approval of this 
protocol as well as assurance that this study will be conducted according to the procedures 
described in the protocol, Good Clinical Practices, and all applicable regulatory 
requirements.
Investigator Agreement: I have read the protocol and agree to conduct the study as 
outlined herein.
Signature:
Date:
Name (print):
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3 SYNOPSIS
Title
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 
Efficacy, Safety, and Dose-Response Study of Lofexidine in the Treatment 
of Opioid Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose 
Lofexidine Treatment (Days 8-14)
Objective
To investigate the efficacy, safety, and dose-response of lofexidine 
hydrochloride (2.4 mg or 3.2 mg per day) in reducing withdrawal signs and 
symptoms and facilitating completion of detoxification/extending treatment 
retention in subjects undergoing detoxification from short-acting opioids in 
a double-blind inpatient setting (Days 1-7) followed by an open-label 
inpatient/outpatient setting (Days 8-14).
Study Design
Two-part, multicenter study in the United States.  The first part of the study 
will use an inpatient, randomized, double-blind, placebo-controlled design, 
which will be followed by a second part, an open-label, continuation 
treatment.
The first part of the study will consist of 7 days of inpatient treatment with 
lofexidine 2.4 mg total daily dose (0.6 mg QID), lofexidine 3.2 mg total 
daily dose (0.8 mg QID), or matching placebo (Days 1-7). During the 
second part of the study (Days 8-14), all subjects, regardless of their 
treatment assignment (which will remain double-blinded), who successfully 
complete Days 1-7, will be eligible to receive open-label, variable dose 
lofexidine treatment as determined by the Site Investigator.  Subjects can be 
treated as inpatients or outpatients during Days 8-14, depending on the 
wishes of the Site Investigator and the subject, for up to an additional 
7 days. No subject will receive lofexidine for more than 14 days total from 
the onset of abstinence.
Sites
~12 (Target: ≥3-4 subjects/site/month. Recruitment time: 12-15 months)
(In the event that the enrollment rate is unsatisfactory, additional centers 
will be added for a total site base of up to 20.)
Inclusion
Criteria
1.
Be male or female at least 18 years of age.
2.
Have current dependence, according to the Mini International
Neuropsychiatric Interview (M.I.N.I.), on any opioid with a half-life
similar to heroin or morphine, including Vicodin®, Lortab®, Lorcet®,
Percocet®, Percodan®, Tylox®, or Hydrocodone (by any route of
administration), or oxycodone (oxycodone and oxycodone time-
released formulation when crushed and snorted, injected or swallowed
after chewing).
3.
Be seeking treatment for opioid dependence.
4.
Have a score ≥2 on the Objective Opiate Withdrawal Scale 
(OOWS-Handelsman) at Baseline.
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Inclusion
Criteria
(continued)
5.
Have reported use of heroin, morphine, or any opioid with a half-life
similar to heroin or morphine for at least 21 of the past 30 days.
6.
Urine toxicology screen positive for opioids and negative for
methadone or buprenorphine.
7.
If female and of childbearing potential, subject must agree to use of
one of the following methods of birth control:
x oral contraceptives;
x patch;
x barrier (diaphragm, sponge or condom) plus spermicidal
preparations;
x intrauterine contraceptive system;
x levonorgestrel implant;
x medroxyprogesterone acetate contraceptive injection;
x complete abstinence from sexual intercourse;
x hormonal vaginal contraceptive ring; or
x surgical sterilization or partner sterile (must have documented 
proof).
8.
Be able to verbalize understanding of the consent form, able to provide
written informed consent, verbalize willingness to complete study
procedures and pass the study consent quiz with 100% accuracy (if
necessary, quiz may be administered more than one time).
Exclusion 
Criteria
1.
Be a female subject who is pregnant or lactating.
2.
Have self-reported use of methadone or buprenorphine in the past
14 days.
3. Have serious medical illnesses including, but not limited to:
x seizures, or those who have received anticonvulsant therapy during
the past 5 years;
x pancreatic disease such as insulin-dependent diabetes;
x liver disease that requires medication or medical treatment, and/or 
aspartate aminotransferase or alanine aminotransferase levels greater 
than 5 times the upper limit of normal;1 and
x gastrointestinal or renal disease, which would significantly impair 
absorption, metabolism or excretion of study drug, or would require 
medication or medical treatment.
4. Have a psychiatric disorder, based on the M.I.N.I., including but not
limited to dementia or any disorder that, in the opinion of the study
physician requires ongoing treatment that would make study
participation unsafe or which would make treatment compliance
difficult.
1 The infectious disease panel for hepatitis will be performed as an aid to determine if the prospective subject has been 
exposed to a hepatitis virus. Positive hepatitis results do not exclude a prospective subject from participation unless 
there is an indication of active liver disease.
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Exclusion 
Criteria 
(continued)
5. Have self-reported acquired immune deficiency syndrome (AIDS).
6. Abnormal cardiovascular exam at screening and before randomization,
including any of the following:
x clinically significant abnormal electrocardiogram (ECG) (e.g., second
or third degree heart block, uncontrolled arrhythmia, or QTcF interval 
greater than 450 msec for males and greater than 470 msec for 
females);
x heart rate less than 55 bpm or symptomatic bradycardia;
x systolic blood pressure less than 95 mmHg or symptomatic 
hypotension;
x diastolic blood pressure less than 65 mmHg;
x blood pressure greater than 155/95 mmHg; and
x prior history of myocardial infarction.
7. Have clinically significant abnormal laboratory values.
8. Requiring any of the following medications currently or within the past
4 weeks:  psychotropics (including sedatives/hypnotics, antidepressants,
neuroleptics), prescription analgesics (excluding those listed in inclusion
criterion #2 above), anticonvulsants, antihypertensives, antiarrhythmics,
antiretroviral, and cholesterol lowering medications.  Nicotine
replacement therapy (patch, inhaler, gum, or nasal spray) is allowed for
nicotine-dependent subjects. Note:  Use of a short-acting
benzodiazepine (e.g., oxazepam) for insomnia during Days 8-14 will not
disqualify a subject.
9. Current dependence (based on the M.I.N.I.) on any psychoactive
substance (other than that listed in inclusion criterion #2, caffeine, or
nicotine) that requires detoxification.
10. Have donated blood within the last 8 weeks.
11. Have participated in an investigational drug study within the past
3 months.
12. Have such “poor” veins that even a single venipuncture cannot be
obtained during screening.
13. Have active tuberculosis (positive tuberculin test and/or confirmatory
diagnostic chest x-ray).
14. Have active syphilis.
N
A sufficient number of subjects will be screened to randomize 600 subjects 
in a 3:3:2 ratio (225 in each lofexidine group and 150 in the placebo group)
at approximately 12 study sites in the US.  The total number of subjects 
randomized at each site will depend on subject availability and will likely
not be evenly distributed at all sites.
Primary 
Endpoint
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
x Area under the curve (AUC) based on Short Opiate Withdrawal Scale 
of Gossop (SOWS-Gossop) scores from Days 1 through 7.
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Secondary 
Endpoint
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
x Completion status (whether a subject receives at least one dose of 
study medication on Day 7 and completes the 3.5-hour post-dose
SOWS-Gossop assessment on Day 7).
Tertiary/
Exploratory 
Endpoints
Days 1-7:  Randomized, Double-Blind, Placebo-Controlled Treatment
x SOWS-Gossop, OOWS-Handelsman, Modified Clinical Global 
Impression (MCGI [Subject and Rater]), Visual Analog Scale for 
Efficacy (VAS-E ), and Clinical Opiate Withdrawal Scale (COWS)
scores on Days 1, 2, 3, 4, 5, 6, and 7;
x Retention analysis (time to removal from study treatment) over the 
7 inpatient days; 
x Status of detoxification on Day 7 or early termination as assessed by 
the Site Investigator;
x Concomitant medication analysis;
x Withdrawal-related adverse event analysis; 
x Evaluation of subject treatment status 30 days post discharge; and
x In addition, single items (e.g., sweating, anxiety) from the OOWS-
Handelsman and COWS that are not included in the SOWS-Gossop 
may be analyzed, as may AUC based on COWS scores from Days 1
through 7.
Days 8-14: Open-Label, Continuation Treatment
x Descriptive evaluation of SOWS-Gossop, OOWS-Handelsman, MCGI 
(Subject and Rater), VAS-E, and COWS;
x Duration of exposure;
x Number/proportion of subjects successfully completing detoxification 
as assessed by the Site Investigator;
x Distribution of number of days required to complete detoxification as 
assessed by the Site Investigator;
x Average daily dose of lofexidine; and
x Concomitant medications.
Duration
21 days (maximum duration per subject, including screening)
Visits
All subjects will undergo screening up to 7 days before study admission.
Days 1-7:  Randomized, Double-Blind, Placebo-Controlled Treatment
x Inpatient confinement on Days 1 through 7
Days 8-14: Open-Label, Continuation Treatment
x Inpatient or daily for up to 7 days if outpatient
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Efficacy 
Assessments
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
The following efficacy assessments will be performed daily at estimated 
time of maximum plasma concentration (i.e., 3.5 hours after the first dose):
x SOWS-Gossop;
x OOWS-Handelsman;
x MCGI (Subject and Rater);
x VAS-E;
x COWS;
x Concomitant medication use; and
x Completion of detoxification as assessed by the Site Investigator (at 
completion of Inpatient Treatment on Day 7 only or, if applicable, 
early termination during Days 1-7).
Days 8-14: Open-Label, Continuation Treatment
The following efficacy assessments will be performed daily before dosing:
x SOWS-Gossop;
x OOWS-Handelsman;
x MCGI (Subject and Rater);
x VAS-E;
x COWS;
x Concomitant medication use; and
x Completion of detoxification as assessed by the Site Investigator.
Safety 
Assessments
Days 1-7: Randomized, Double-Blind, Placebo-Controlled Treatment
The following safety assessments will be performed daily:
x Occurrence, seriousness, severity, and causality assessment of 
adverse events (AEs);
x Vital signs (sitting/standing blood pressure and pulse) before every 
dose and 3.5 hours after administration of study medication at 8 AM, 
1 PM, and 6 PM (7 times/day);
x 12-lead ECGs (in duplicate) will be done before the first daily dose, 
pre-1 PM dose, at 4 PM, and at 5 PM on Days 1 and 7; before the first 
daily dose only on Days 2 and 4; and, if applicable, early termination 
during Days 1-7.
x Clinical laboratory tests as clinically warranted and at discharge or
early termination during Days 1-7;
x Finger prick blood sample for pharmacokinetic (PK) analysis will be 
collected concurrently with each scheduled ECG during Days 1-7; and
x Physical examination at Baseline (update of Screening exam), a 
complete exam 3 to 4 hours after randomization on Day 1 and at 
discharge or early termination during Days 1-7.
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Safety 
Assessments 
(continued)
In addition, qualitative urine drug screening (by on-site use of “dipsticks”) 
will be done at least every other day to monitor for contraband.
Days 8-14: Open-Label, Continuation Treatment
The following safety assessments will be performed daily:
x Occurrence, seriousness, severity, and causality assessment of AEs;
x Vital signs (sitting blood pressure and pulse) at least once daily
before dosing and 3.5 hours after dosing;
x 12-lead ECGs (in duplicate) will be done before the first daily dose 
and at 11:30 AM on Days 8 and 14 or, if applicable, early 
discharge/termination from the study.
x Clinical laboratory tests as clinically warranted and on Day 14 or, if 
applicable, early discharge/termination from the study; 
x Complete physical examination as clinically warranted and on Day 14
or, if applicable, early discharge/termination from the study; and
x Pregnancy test on Day 14 or, if applicable, early 
discharge/termination from the study.
Qualitative urine drug screening (by on-site use of “dipsticks”) will be done 
at least every other day to monitor for illicit drug use.
A 30-day post discharge follow-up telephone contact will be made for an 
adverse event evaluation and an evaluation of the subject’s current treatment 
status (e.g., relapse, current psychosocial treatment, successful entry into a 
methadone, buprenorphine, or naltrexone program).
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4 TABLE OF CONTENTS
1 
PROTOCOL AMENDMENT SUMMARY...................................................................2 
2 
SIGNATURE PAGE.......................................................................................................6 
3 
SYNOPSIS......................................................................................................................7 
4 
TABLE OF CONTENTS..............................................................................................13 
5 
ABBREVIATIONS AND DEFINITION OF TERMS.................................................18 
6 
BACKGROUND AND SIGNIFICANCE ....................................................................19 
6.1 
Opioid Dependence ..................................................................................................19 
6.2 
Lofexidine Hydrochloride ........................................................................................20 
6.3 
Efficacy of Lofexidine .............................................................................................21 
6.4 
Safety of Lofexidine.................................................................................................22 
6.5 
Rationale for Dose Selection and Regimen..............................................................22 
6.6 
Rationale for Outcome Measures.............................................................................23 
7 
STUDY OBJECTIVES.................................................................................................23 
8 
STUDY SPONSOR ......................................................................................................24 
9 
STUDY SITES AND INVESTIGATORS ...................................................................24 
10 
INVESTIGATIONAL PLAN .......................................................................................24 
10.1 
Overall Design..........................................................................................................24 
10.2 
Number of Subjects..................................................................................................25 
10.3 
Duration of Study .....................................................................................................25 
11 
SELECTION OF STUDY POPULATION ..................................................................25 
11.1 
Population Base........................................................................................................25 
11.2 
Study Entrance Requirements ..................................................................................25 
11.2.1 
Inclusion Criteria.................................................................................................25 
11.2.2 
Exclusion Criteria................................................................................................26 
11.3 
Screening Failures ....................................................................................................28 
12 
INVESTIGATIONAL AGENTS..................................................................................28 
12.1 
Lofexidine Hydrochloride ........................................................................................28 
12.2 
Placebo .....................................................................................................................29 
12.3 
Dispensing Investigational Agents...........................................................................29 
12.4 
Blinding Plan............................................................................................................29 
12.5 
Labeling....................................................................................................................30 
12.6 
Storage......................................................................................................................31 
12.7 
Record of Administration.........................................................................................31 
12.8 
Used/Unused Supplies..............................................................................................31 
12.9 
Contraindications .....................................................................................................32 
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13 
TREATMENT PLAN ...................................................................................................32 
13.1 
Investigational Agents..............................................................................................32 
13.2 
Dose Administration ................................................................................................32 
13.2.1 
Administration of Doses......................................................................................32 
13.2.2 
Dose-Hold Criteria ..............................................................................................33 
13.2.3 
Discontinuation Criteria ......................................................................................34 
13.3 
Treatment Compliance .............................................................................................34 
13.4 
Nicotine Replacement Therapy................................................................................34 
14 
STUDY PROCEDURES ..............................................................................................35 
14.1 
Subject Recruitment and Consent ............................................................................35 
14.2 
Screening..................................................................................................................36 
14.3 
Treatment Phase .......................................................................................................36 
14.3.1 
Baseline ...............................................................................................................36 
14.3.2 
Subject Randomization........................................................................................36 
14.3.3 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment) ............36 
14.3.4 
Days 8-14 (Open-Label, Continuation Treatment) .............................................37 
14.3.5 
Maintaining and Breaking the Blind ...................................................................37 
14.4 
Subject Reimbursement............................................................................................37 
14.5 
Study Termination....................................................................................................38 
14.5.1 
Subject Termination ............................................................................................38 
14.5.2 
Cardiovascular Events Requiring Subject Termination From Study ..................39 
14.5.3 
Trial Discontinuation...........................................................................................40 
14.6 
Concomitant Therapy...............................................................................................40 
15 
CLINICAL EVALUATIONS.......................................................................................41 
15.1 
Screening Assessments ............................................................................................44 
15.2 
Baseline Assessments...............................................................................................44 
15.3 
Assessments During Treatment................................................................................45 
15.3.1 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment) ............45 
15.3.2 
Days 8-14 (Open-Label, Continuation Treatment) .............................................46 
15.4 
Efficacy Assessment Methods .................................................................................47 
15.4.1 
Short Opiate Withdrawal Scale (SOWS-Gossop) ...............................................47 
15.4.2 
Objective Opiate Withdrawal Scale (OOWS-Handelsman)................................47 
15.4.3 
Modified Clinical Global Impressions Scale (MCGI).........................................48 
15.4.4 
Visual Analog Scale for Efficacy (VAS-E).........................................................49 
15.4.5 
Clinical Opiate Withdrawal Scale (COWS) ........................................................49 
15.4.6 
Assessment of Completion of Detoxification......................................................50 
15.4.7 
Concomitant Medication Use ..............................................................................50 
15.4.8 
Withdrawal-Related Adverse Events ..................................................................50 
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15.4.9 
Subject Treatment Status 30 Days Post Discharge..............................................50 
15.5 
Safety Assessment Methods.....................................................................................50 
15.5.1 
Adverse Events....................................................................................................50 
15.5.2 
Vital Signs ...........................................................................................................51 
15.5.3 
12-Lead Electrocardiograms ...............................................................................52 
15.5.4 
Clinical Laboratory Evaluations..........................................................................53 
15.5.4.1 
Standard Laboratory Tests..............................................................................53 
15.5.4.2 
Infectious Disease Panel and Syphilis Tests...................................................54 
15.5.4.3 
Urine Toxicology Screening...........................................................................55 
15.5.4.4 
Pregnancy Test................................................................................................55 
15.5.4.5 
Pharmacokinetic Sampling .............................................................................55 
15.5.5 
Physical Examination ..........................................................................................55 
15.6 
Other Assessments ...................................................................................................55 
15.6.1 
Prior Medications ................................................................................................55 
15.6.2 
Concomitant Medication Administration ............................................................55 
16 
REGULATORY AND REPORTING REQUIREMENTS...........................................56 
16.1 
Good Clinical Practices............................................................................................56 
16.2 
FDA Form 1572 and Financial Disclosure ..............................................................56 
16.3 
Institutional Review Board Approval ......................................................................56 
16.4 
Informed Consent/HIPAA Authorization ................................................................57 
16.5 
Drug Accountability.................................................................................................57 
16.6 
Outside Monitoring ..................................................................................................57 
16.6.1 
Data and Safety Monitoring Board (DSMB).......................................................57 
16.6.2 
Medical Monitor..................................................................................................58 
16.6.3 
Clinical Monitors.................................................................................................58 
16.7 
Adverse Event Reporting .........................................................................................58 
16.8 
Serious Adverse Events (SAEs)...............................................................................59 
16.8.1 
Clarification of Serious Adverse Events .............................................................60 
16.9 
Overdose...................................................................................................................61 
16.10 
Pregnancy .................................................................................................................61 
17 
STATISTICAL APPROACH .......................................................................................61 
17.1 
General Considerations ............................................................................................61 
17.2 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment).................61 
17.2.1 
Analysis Populations ...........................................................................................62 
17.2.2 
Demographics and Baseline Characteristics .......................................................62 
17.2.3 
Subject Disposition..............................................................................................62 
17.2.4 
Primary Efficacy Endpoint ..................................................................................62 
17.2.5 
Secondary Efficacy Endpoint ..............................................................................62 
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17.2.6 
Tertiary/Exploratory Endpoints...........................................................................62 
17.2.7 
Control of the False Positive Rate and Statistical Testing Strategy ....................63 
17.2.8 
Statistical Methods for Efficacy ..........................................................................63 
17.2.8.1 
SOWS-Gossop AUC(1-7) ..............................................................................63 
17.2.8.2 
Completion Status...........................................................................................65 
17.2.8.3 
SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7................................................65 
17.2.8.4 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS.........65 
17.2.8.5 
Retention Analysis (Time to Removal from Study Treatment)......................65 
17.2.8.6 
Concomitant Medication Analysis .................................................................66 
17.2.8.7 
Status of Detoxification on Day 7 or Early Termination as Assessed by 
the Site Investigator ........................................................................................66 
17.2.8.8 
Single Items from the OOWS-Handelsman and COWS, and COWS 
AUC(1-7)........................................................................................................66 
17.2.9 
Power Calculations..............................................................................................66 
17.2.10 Subgroup Analyses..............................................................................................67 
17.2.11 Safety Measures...................................................................................................67 
17.3 
Days 8-14 (Open-Label, Continuation Treatment) ..................................................67 
17.3.1 
Assessment of Effectiveness ...............................................................................67 
17.3.2 
Assessment of Safety...........................................................................................68 
18 
DATA MANAGEMENT AND CASE REPORT FORMS (CRFS) ............................68 
18.1 
Data Collection.........................................................................................................68 
18.2 
Electronic Data Capture ...........................................................................................69 
18.3 
Data Analysis ...........................................................................................................69 
18.4 
Study Documentation and Records Retention .........................................................69 
18.5 
Confidentiality..........................................................................................................70 
18.5.1 
Confidentiality of Data........................................................................................70 
18.5.2 
Confidentiality of Subject Records .....................................................................70 
19 
PUBLICATIONS OF THE STUDY RESULTS ..........................................................70 
20 
PROTOCOL ADHERENCE AND AMENDMENTS..................................................71 
21 
QUALITY CONTROL AND QUALITY ASSURANCE............................................72 
22 
REFERENCES..............................................................................................................72 
TABLES
Table 1. Schedule of Study Assessments ...............................................................................42 
Table 2. SOWS-Gossop Scoring Method...............................................................................47 
Table 3. OOWS-Handelsman Scoring Method......................................................................48 
Table 4. MCGI Scoring Method.............................................................................................49 
Table 5. Hematology, Chemistry, and Urinalysis Tests.........................................................54 
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APPENDICES
Appendix 1 
Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop)
Appendix 2 
Objective Opiate Withdrawal Scale of Handelsman (OOWS-Handelsman) 
Appendix 3 
Modified Clinical Global Impression (MCGI)
Appendix 4 
Visual Analog Scale for Efficacy (VAS-E)
Appendix 5 
Clinical Opiate Withdrawal Scale (COWS)
Appendix 6 
Instructions for Evaluating and Reporting Adverse Events and Serious 
Adverse Events
Appendix 7 
Procedure for Applying for a Certificate of Confidentiality 
Appendix 8 
Outpatient Vital Signs Diary
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5 ABBREVIATIONS AND DEFINITION OF TERMS
AE(s)
Adverse Event(s)
AIDS
Acquired Immune Deficiency Syndrome
ALT/SGPT
Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase
Anti-HBc
Hepatitis B Core Antibody
Anti-HBs
Hepatitis B Surface Antibody
AUC
Area Under the Concentration-Time Curve
AST/SGOT
Aspartate Aminotransferase/Serum Glutamic-Oxaloacetic 
Transaminase
BP
Blood Pressure
bpm
beats per minute
BUN
Blood Urea Nitrogen
CAP
College of American Pathologists
CFR
Code of Federal Regulations
CLIA
Clinical Laboratory Improvement Act of 1988
CO2
Carbon Dioxide
COWS
Clinical Opiate Withdrawal Scale
CRF(s)
Case Report Form(s)
CRO
Clinical Research Organization
DAWN
Drug Abuse Warning Network
DBP
Diastolic Blood Pressure
DHHS
Department of Health and Human Services
DSMB
Data and Safety Monitoring Board
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders - Fourth 
Edition
ECG
Electrocardiogram
eCRF(s)
Electronic Case Report Form(s)
EDC
Electronic Data Capture
FDA
Food and Drug Administration
FWE
Familywise Error Rate
GCP
Good Clinical Practices
GGT
Gamma-Glutamyl Transpeptidase
Hbs Ag
Hepatitis B Surface Antigen
HCV Ab
Hepatitis C Virus Antibody
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intent-To-Treat
LDH
Lactate Dehydrogenase
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
MCGI
Modified Clinical Global Impression
MHOWS
Modified Himmelsbach Opiate Withdrawal Scale
M.I.N.I.
Mini International Neuropsychiatric Interview
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mITT
Modified Intent-To-Treat
mmHg
Millimeters of Mercury
msec
Millisecond
NDA
New Drug Application
NIMH
National Institute of Mental Health
OOWS-Handelsman
Objective Opiate Withdrawal Scale of Handelsman
PK
Pharmacokinetic
PPD
Purified Protein Derivative (skin test for tuberculosis)
PRN
As Needed
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QID
Four Times Daily
QT
QT interval of an electrocardiogram
QTc
Corrected QT interval
QTcB
Corrected QT interval – Bazett’s method
QTcF
Corrected QT interval – Fridericia’s method
QTcI
Individually corrected QT interval
RBC
Red Blood Cell
RPR
Rapid Plasma Reagin
SAE(s)
Serious Adverse Event(s)
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SOWS-Gossop
Short Opiate Withdrawal Scale of Gossop
T4
Free Thyroxine
Tmax
Time of Maximum Plasma Drug Concentration
TSH
Thyroid-Stimulating Hormone
UDS
Urine Drug Screening
UK
United Kingdom
ULN
Upper Limit of Normal
US
United States
USWM
US WorldMeds, LLC
VAS-E
Visual Analog Scale for Efficacy
WBC
White Blood Cell
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7 STUDY OBJECTIVES
The primary objective of this study is to investigate the efficacy, safety, and dose-response of 
lofexidine (2.4 mg or 3.2 mg per day) in reducing withdrawal signs and symptoms and 
facilitating completion of detoxification/extending treatment retention in subjects undergoing 
detoxification from short-acting opioids in a double-blind inpatient setting (Days 1-7) 
followed by an open-label inpatient/outpatient setting (Days 8-14).
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It is hypothesized that a daily dose of either 2.4 mg or 3.2 mg lofexidine will achieve greater 
efficacy than placebo with respect to overall symptom relief over the first 7 days of opioid 
withdrawal (primary endpoint) and will increase the likelihood of subjects completing 
Days 1-7 of treatment (secondary endpoint). Further, safety measures in the 2.4 mg and 
3.2 mg total daily dose groups will be compared descriptively to assess whether the lower 
dose results in fewer and less severe adverse events than does the higher dose.
8 
  
STUDY 
         SPONSOR
This study will be conducted under an Investigational New Drug (IND) application (#47,857) 
held by US WorldMeds, LLC.
9 STUDY SITES AND INVESTIGATORS
This study will be conducted at approximately 12 study sites in the US. In the event that the 
enrollment rate is unsatisfactory, additional centers will be added for a total site base of up to 
20. It is the responsibility of the Site Investigators to make sure this protocol is conducted in 
full conformance with the ethical principles detailed in Section 16 of this protocol. All data 
will be collected at the study sites on source documents and entered at the site into electronic 
case report forms (eCRFs) as described in Section 18.1 of this protocol.
10 INVESTIGATIONAL PLAN
10.1 Overall Design
This is a Phase 3, two-part, multicenter study to evaluate the dose-response, efficacy, and 
safety of lofexidine in alleviation of symptoms in subjects undergoing total and abrupt 
withdrawal from short-acting opioids. Any subject dependent on short-acting opioids (the 
primary projected indication for lofexidine) about to undergo opioid withdrawal will be 
eligible. Subjects will be evaluated for their compliance with protocol inclusion/exclusion 
criteria during a screening period, lasting up to 7 days.
The first part of the study will use an inpatient, randomized, double-blind, and placebo-
controlled design (Days 1-7) followed by a second part, an open-label, continuation treatment 
(Days 8-14). A total of 600 subjects will be randomized to receive lofexidine 2.4 mg total 
daily dose (0.6 mg QID), lofexidine 3.2 mg total daily dose (0.8 mg QID), or matching 
placebo in a 3:3:2 ratio (225:225:150) for 7 days (i.e., during the most intense stage of 
withdrawal).  During the second part of the study (Days 8-14), all subjects, regardless of their 
treatment assignment (which will remain double-blinded), who successfully meet the 
definition for “completer” based on Days 1-7 (i.e., receives at least one dose of study 
medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop assessment on 
Day 7), will be eligible to receive open-label, variable dose lofexidine treatment (as 
determined by the Site Investigator, but not to exceed 3.2 mg/day) for up to an additional 
7 days in either an inpatient or outpatient setting depending on the wishes of the investigator 
and the subject. No subject will receive lofexidine for more than 14 days total from the onset 
of abstinence. There will be no initial dose run-up and no mandated terminal dose taper. 
Efficacy and safety assessments will be made daily (see detailed Schedule of Assessments in 
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Table 1 of Section 15). Qualitative urine drug screening will be done every other day to 
monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
10.2 Number of Subjects
A sufficient number of subjects will be screened to randomize 600 subjects (225 in each 
lofexidine group and 150 in the placebo group) at approximately 12 study sites in the US
(should the enrollment rate be unsatisfactory, additional centers will be added for a total site 
base of up to 20).  The total number of subjects randomized at each site will depend on 
subject availability and will likely not be evenly distributed across all sites.
10.3 Duration of Study
The maximum duration of participation for each subject in this study will be 21 days, 
including the Screening/Baseline period, which can last up to 7 days, followed by up to 
14 days of treatment with study medication (lofexidine and/or placebo).
During Inpatient Treatment (Days 1-7), randomized subjects will receive lofexidine 2.4 mg 
total daily dose (0.6 QID), lofexidine 3.2 mg total daily dose (0.8 QID), or matching placebo 
treatment for up to 7 days. For Days 8-14, subjects will receive open-label, variable dose 
lofexidine for up to 7 additional days (open-label, continuation treatment). Full 
randomization into the study is anticipated to take 12 to 15 months to achieve (3-4 subjects 
per month per site), with the total clinical duration of the study anticipated to be 15 to 
18 months.
11 SELECTION OF STUDY POPULATION
11.1 Population Base
Any opioid-dependent subject about to undergo withdrawal from short-acting opioids will be 
evaluated for study eligibility after providing written informed consent. Entry into this study 
is open to both men and women and to all racial and ethnic subgroups.  An attempt will be 
made to include at least 25% female subjects and a mix of ethnicities reflecting the 
distribution in the local geographic regions of the study sites. Subjects will be recruited from 
a variety of sources, including subjects seeking treatment for opioid dependence via referrals 
from local treatment providers, word of mouth among subjects themselves also seeking 
treatment, and advertising in the local media. Recruitment advertisements will be approved 
by each site’s Institutional Review Board (IRB).
Potential subjects may be accepted for screening after the nature and purpose of the 
investigation have been explained to them and after they have voluntarily given written 
informed consent (see Section 16.4).
11.2 Study Entrance Requirements
11.2.1 
Inclusion Criteria
To be eligible for participation, subjects must meet all of the following criteria:
1. Be male or female at least 18 years of age.
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2. Have current dependence, according to the Mini International Neuropsychiatric 
Interview (M.I.N.I.) [17, 18], on any opioid with a half-life similar to heroin or 
morphine, including Vicodin®, Lortab®, Lorcet®, Percocet®, Percodan®, Tylox®, 
or Hydrocodone (by any route of administration), or oxycodone (oxycodone and 
oxycodone time-released formulation when crushed and snorted, injected or 
swallowed after chewing).
3. Be seeking treatment for opioid dependence.
4. Have a score ≥2 on the Objective Opiate Withdrawal Scale (OOWS–Handelsman) at 
Baseline.
5. Have reported use of heroin, morphine, or any opioid with a half-life similar to heroin 
or morphine for at least 21 of the past 30 days.
6. Urine toxicology screen positive for opioids but negative for methadone and 
buprenorphine.
7. If female and of childbearing potential, subject must agree to use of one of the 
following methods of birth control: 
x
oral contraceptives;
x
patch;
x
barrier (diaphragm, sponge or condom) plus spermicidal preparations;
x
intrauterine contraceptive system;
x
levonorgestrel implant;
x
medroxyprogesterone acetate contraceptive injection;
x
complete abstinence from sexual intercourse;
x
hormonal vaginal contraceptive ring; or
x
surgical sterilization or partner sterile (must have had documented proof).
8. Be able to verbalize understanding of the consent form, able to provide written
informed consent, verbalize willingness to complete study procedures, and pass the
study consent quiz with 100% accuracy (if necessary, quiz may be administered more
than one time).
11.2.2 
Exclusion Criteria
Subjects who meet any of the following criteria will not be allowed to participate:
1. Be a female subject who is pregnant or lactating.
2. Have self-reported use of methadone or buprenorphine in the past 14 days.
3. Have serious medical illnesses including, but not limited to:
x
seizures, or those who have received anticonvulsant therapy during the past
5 years;
x
pancreatic disease such as insulin-dependent diabetes;
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x
liver disease that requires medication or medical treatment, and/or aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than 
5 times the upper limit of normal;2 and
x
gastrointestinal or renal disease, which would significantly impair absorption, 
metabolism or excretion of study drug, or would require medication or medical 
treatment.
4. Have a psychiatric disorder, based on the M.I.N.I., including but not limited to
dementia or any disorder that, in the opinion of the study physician requires ongoing
treatment that would make study participation unsafe or which would make treatment
compliance difficult.
5. Have self-reported acquired immune deficiency syndrome (AIDS).
6. Abnormal cardiovascular exam at screening and before randomization, including any
of the following:
x
clinically significant abnormal electrocardiogram (ECG) (e.g., second or third
degree heart block, uncontrolled arrhythmia, or QTcF interval greater than 
450 msec for males and greater than 470 msec for females);
x
heart rate less than 55 bpm or symptomatic bradycardia;
x
systolic blood pressure (SBP) less than 95 mmHg or symptomatic hypotension;
x
diastolic blood pressure (DBP) less than 65 mmHg;
x
blood pressure (BP) greater than 155/95 mmHg; and
x
prior history of myocardial infarction.
7. Have clinically significant abnormal laboratory values.
8. Requiring any of the following medications currently or within the past 4 weeks:
psychotropics (including sedatives/hypnotics, antidepressants, neuroleptics),
prescription analgesics (excluding those listed in inclusion criterion #2 above),
anticonvulsants, antihypertensives, antiarrhythmics, antiretroviral, and cholesterol
lowering medications.  Nicotine replacement therapy (patch, inhaler, gum, or nasal
spray) will be allowed for nicotine-dependent subjects.
Note:  Use of a short-acting benzodiazepine (e.g., oxazepam) for insomnia during
Days 8-14 will not disqualify a subject.
9. Current dependence (based on the M.I.N.I.) on any psychoactive substance (other
than that listed in inclusion criterion #2, caffeine or nicotine) that requires
detoxification.
10. Have donated blood within the last 8 weeks.
11. Have participated in an investigational drug study within the past 3 months.
12. Have such “poor” veins that even a single venipuncture cannot be obtained during
screening.
2 The infectious disease panel for hepatitis will be performed as an aid to determine if the prospective subject has been 
exposed to a hepatitis virus. Positive hepatitis results do not exclude a prospective subject from participation unless 
there is an indication of active liver disease.
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13. Have active tuberculosis (positive tuberculin test and/or confirmatory diagnostic
chest x-ray).
14. Have active syphilis.
Notes on inclusion/exclusion criterion: Potential subjects who are positive for syphilis by a 
treponemal-specific test (FTA-ABS or MHA-TP) will not be eligible for study participation 
and will be referred for appropriate follow-up and/or treatment, if required.
The infectious disease panel for hepatitis is performed as an aid to determine if the 
prospective subject has been exposed to a hepatitis virus. Positive hepatitis results do not 
exclude a prospective subject from participation unless there is an indication of active liver 
disease.
Tuberculin test (purified protein derivative [PPD]) and/or a chest x-ray will be performed on 
all subjects. A positive PPD result does not exclude a prospective subject from participation,
but if diagnostic tests (e.g., chest x-ray) indicate that active disease is present, subjects will 
be excluded from participation.
If any tests are positive, the subject will be notified of the test results and referred for 
treatment.
11.3 Screening Failures
Screening failures are potential study subjects who provide informed consent and fail 
inclusion and/or exclusion criteria or for other reasons are not allowed to participate. A
screening log for all subjects who are screened will be maintained. The screening log will 
uniquely identify each subject and report whether he or she passed or failed screening, and, if 
he or she did not pass, the reasons for the screening failure.
Subjects who fail screening for any reason cannot be rescreened for study participation at a 
later time.
12 INVESTIGATIONAL AGENTS
12.1 Lofexidine Hydrochloride
Lofexidine hydrochloride is an D2-adrenergic agonist with mild to moderate antihypertensive 
actions. It has the empirical formula C11H13Cl3N2O representing a molecular weight of 
295.61. The structural formula is:
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Lofexidine hydrochloride is a synthetic product and has the chemical designation of 2-[1-
(2,6-dichlorophenoxy)ethyl]-4,5 dihydro-1H- imidazole monohydrochloride.  It is a white to
off-white crystalline powder that is very soluble in water and ethanol.  It is lightly soluble in 
2-propanol and practically insoluble in ether.  Lofexidine hydrochloride melts at 
approximately 126-128°C.
Lofexidine will be supplied by the Sponsor (USWM) in peach colored tablets containing 
0.2 mg of active medication for oral administration.
Lofexidine should be stored at room temperature in a secure area.
12.2 Placebo
Placebo will be supplied by the Sponsor (USWM) as an exact match of lofexidine, less the 
active ingredient.
12.3 Dispensing Investigational Agents
All investigational agents will be distributed from 
(the pharmacy 
coordinating center) in “Subject Kits.”
For the Inpatient Treatment part of the study (Days 1-7), a supply of unassigned subject kits 
will be maintained at each participating site.  Each subject kit will contain 7 blister cards 
(packaged by 
 with the appropriate dosing of lofexidine and/or matched 
placebo for each day of the inpatient phase of the study.
For Days 8-14 (open-label treatment), lofexidine tablets will be supplied in uniquely-
identified 80-count bottles, which will be dispensed by the study pharmacist as determined 
clinically appropriate by the Site Investigator to the subject in individual prescription bottles 
containing their doses for only the following 1 or 2 days, as appropriate.  The site will 
maintain a dispensing log for each bottle and document the number of tablets dispensed to 
each subject along with the number of tablets returned, if any, by the subject at each 
outpatient visit.  Returned tablets will not be re-dispensed to future subjects.
All study medications will be dispensed by the site pharmacists to the Site Investigators or 
their designee.
12.4 Blinding Plan
The subjects, Site Investigators, site personnel, Sponsor (USWM), and clinical personnel at 
the CRO 
including the biostatistician will be blinded to 
medication assignment groups.  The study pharmacist at the central pharmacy 
 
and bioanalytical personnel at the CRO will not be blinded to medication 
assignment.  The bioanalytical personnel will not be blinded because they will need to 
identify finger-prick pharmacokinetic samples from placebo subjects; these samples will not 
be analyzed.
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The investigational agents, lofexidine (2.4 mg or 3.2 mg) and placebo, will be packaged in 
blister cards of matched appearance and labeling for the Inpatient Treatment part of the study 
(Days 1-7). Days 8-14 will be open-label, although subjects’ treatment assignment during 
Days 1-7 will remain blinded. Refer to Section 14.3.5 should breaking the blind become 
necessary for the safety of the subject.
12.5 Labeling
The investigational agents, lofexidine and placebo, will be packaged in blister cards for the 
Inpatient Treatment part of the study (Days 1-7) and further packaged in an outer carton 
(blister card kit).  Lofexidine will be packaged in bottles for Days 8-14 (open-label 
treatment).
The blister card kit (outer carton) will be labeled with the following information:
x
subject randomization number,
x
space for site personnel to enter subject initials/name code,
x
name of study,
x
protocol number,
x
number of tablets (per card and total for kit),
x
name/address of the pharmacy coordinating center 
 
x
24-hour emergency telephone number, and
x
the following statement – “Caution: New Drug – Limited by Federal Law to 
Investigational Use.”
The individual blister card labels will include the following information:
x
subject randomization number,
x
space for site personnel to enter subject initials/ name code,
x
name of study,
x
protocol number,
x
study day (e.g., Day 1, Day 2) and each row of tablets will be delineated with dosing 
times (i.e., 8AM, 1PM, 6PM, 11PM) to ensure that the appropriate tablets are given at 
each protocol-specified dosing time, and
x
a description of the investigational product:  “Lofexidine HCl 2.4 mg, Lofexidine HCl 
3.2 mg, or Placebo,” thus identifying the drug but preserving the blind.
The bottle product label will include the following information:
x
name of study,
x
protocol number,
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x
a unique bottle number for purposes of investigational product accountability, and
x
a description of the investigational product, i.e., “Lofexidine HCl 0.2 mg tablets” as 
the portion of the study that will use bottled study drug under open-label conditions.
In the open-label phase of the study (Days 8-14), sites may dispense 1 to 2 days of 
investigational product to the subject for use in an outpatient setting.  In such cases, the 
redispensing container will include a subject label, supplied by the study site, and will 
include the following information:
x
name of study,
x
protocol number,
x
subject initials,
x
subject randomization number,
x
study physician’s name,
x
site emergency contact telephone number,
x
description of the medication (i.e., “Lofexidine HCl 0.2 mg tablets”), 
x
number of tablets dispensed,
x
directions for use, and
x
the name/address of the pharmacy coordinating center 
12.6 Storage
Investigational agents will be stored at room temperature in a secure location at the 
dispensing pharmacy.
12.7 Record of Administration
Accurate recording of all investigational agents received, dispensed, administered, and 
returned will be maintained by study site personnel.
12.8 Used/Unused Supplies
At the end of the study, all unused investigational agents must be inventoried. If any 
investigational agent is lost or damaged, its disposition should be documented. Unused 
investigational agents will be retained at the participating sites to enable a full investigational 
drug inventory by the sites’ respective monitors.  Sponsor will provide instructions to return 
the unused study drug to the pharmacy coordinating center periodically throughout the study 
(following monitor review) or at the end of the study for proper destruction in accordance 
with local and federal regulations.
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12.9 Contraindications
To avoid drug-drug interactions, lofexidine should not be administered concurrently with:
x
tricyclic antidepressants – may reduce the efficacy of imidazoline derivatives;
x
alcohol, sedatives, and anaesthetics – may interact with lofexidine and enhance its central 
sedative effects; and
x
beta-receptor blockers – the combination of lofexidine and beta-receptor blockers should 
be used with caution to avoid the risk of excessive bradycardia.
13 TREATMENT PLAN
13.1 Investigational Agents
On Day 1 of the Inpatient Treatment part of the study, subjects will be randomized to one of 
two dose levels of lofexidine or placebo and receive the following daily treatment regimens 
through Day 7: lofexidine 2.4 mg/day (administered as 3 x 0.2 mg tablets and 1 placebo 
tablet QID), lofexidine 3.2 mg/day (administered as 4 x 0.2 mg tablets QID), or matching 
placebo (administered as 4 x placebo tablets QID). In order to maintain the treatment blind, 
all subjects will receive a total of 16 tablets per day whether active, placebo, or in 
combination to achieve the assigned dose.  Tablets will be provided in subject-specific kits, 
containing 7 blister cards (one for each study day).  Each blister card will contain 4 rows of 
4 tablets each, appropriately marked to indicate which row of tablets should be administered 
at each of the specified dosing times (8 AM, 1 PM, 6 PM, and 11 PM).  Dose kits for subjects 
randomized to lofexidine 3.2 mg/day will contain full blister cards of active tablets.  Dose 
kits for subjects randomized to lofexidine 2.4 mg/day will contain blister cards in which each 
dose row contains 3 active tablets and 1 placebo tablet.  Dose kits for subjects randomized to 
placebo will contain full blister cards of placebo tablets.
For the Open-Label, Continuation Treatment part of the study (Days 8-14), subjects will 
receive lofexidine at variable dose, as determined by the Site Investigator (see Section 13.2).
13.2 Dose Administration
13.2.1 
Administration of Doses
During Inpatient Treatment (Days 1-7), subjects must take study medication orally, within a 
30-minute window, 15 minutes before or after 8 AM, 1 PM, 6 PM, and 11 PM.  The actual 
date and time of each dose will be recorded in the subject’s source document and on the 
eCRF.  Placebo will appear identical to lofexidine. Blood pressure and pulse (both sitting 
and standing) will be measured before each dose and 3.5 hours after each dose (with the 
exception of the dose taken at 11 PM, where the measurement at 3.5 hours post-dose will not 
be done).  Details for obtaining vital sign are provided in Section 15.5.2.
During Open-Label, Continuation Treatment (Days 8-14), there will be no mandated 
lofexidine dose regimen and subjects may receive lofexidine treatment during this time in 
either an inpatient or outpatient setting depending on the wishes of the Site Investigator and 
the subject. The rationale for the decision to continue treatment or not and the Site 
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Investigator’s decision to continue treatment through either an inpatient or outpatient setting 
must be documented in the subject’s source document. The dose regimen will be determined 
by the Site Investigators as clinically indicated for relief of subjects’ symptoms, with 
supporting rationale for any dose changes recorded in the subject’s source document.  In no 
case is the dose of lofexidine to exceed 3.2 mg/day (or a single dose of 0.8 mg).  Previous 
studies have shown that dose titration is not necessary to reach a maximum intended dose.  
Also, abrupt withdrawal of lofexidine has not been found to have any significant safety 
issues.  Nevertheless, a dose taper may be appropriate given the dissipating severity of 
symptoms in the later days of withdrawal.  During Days 8-14, blood pressure and pulse (both 
sitting and standing) should be assessed for one dose every day at pre-dose and 3.5 hours 
post-dose.
As further guidance, the dosing regimen recommended for lofexidine (BritLofex™) in the 
UK is as follows:
“The dosage of lofexidine should be titrated according to the patient’s response.  Initial 
dosage should be 0.8 mg per day in divided doses.  The dosage may be increased by 
increments of 0.4 to 0.8 mg per day up to a maximum of 2.4 mg daily.  Maximum single 
dose should not exceed 4 x 0.2 mg tablets (0.8 mg).  Each patient should be assessed on an 
individual basis; those undergoing acute detoxification will usually require the highest 
recommend dose and dosage increments to provide optimum relief at the time of expected 
peak withdrawal symptoms.”
The lower maximum dose allowed in the UK (2.4 mg/day) may be reflective of the less 
severe opioid dependence experienced by patients in the UK. US studies have shown that 
3.2 mg/day can be safely administered (see Sections 6.3 and 6.4).
Note:  In order to prevent dehydration from opioid withdrawal, increased fluid intake will be 
encouraged from the beginning of the study.  Instances in which study medication is not 
administered within the 30-minute windows as noted above will be documented as protocol 
deviations.
13.2.2 
Dose-Hold Criteria
Study medication will be held if vital signs meet any of the following criteria:
Recumbent
x
Systolic blood pressure <90 mmHg and >20% below screen value;
x
Diastolic blood pressure <50 mmHg and >20% below screen value;
x
Heart rate <50 bpm and >20% below screen value; and
x
Symptoms of hypotension and/or bradycardia (e.g., lightheadedness, dizziness, 
syncope).
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Orthostatic (after standing for 3 minutes)
x
Systolic blood pressure diastolic blood pressure, or pulse >25% below 
recumbent values.
All instances of dose-holds must be clearly documented in the subject’s source document.
13.2.3 
Discontinuation Criteria
A subject will be discontinued from the study if any of the following criteria are met:
x
Systolic blood pressure <70 mmHg and >20% below screen value;
x
Diastolic blood pressure <40 mmHg and >20% below screen value;
x
Heart rate <40 bpm and >20% below screen value;
x
QTcF >500 msec3 or >25% above screen value for both males and females;
x
Syncope;
x
Subject misses 2 doses in 24 hours;
x
Subject misses a total of 6 doses during Days 1-7 of the study; and
x
Concomitant medication use (other than alumina, magnesia, and simethicone) for 
intolerable nausea and emesis.
Additional discontinuation criteria based on cardiovascular events are provided in 
Section 14.5.2.
13.3 Treatment Compliance
Each of the inpatient doses during Days 1-7 will be observed by the site staff.  Following 
administration of the oral study medication, hand and mouth checks will be performed to 
ensure that the dose is swallowed. In an inpatient setting during Days 8-14, each dose will be 
observed by study staff and hand and mouth checks will be performed.  In an outpatient 
setting during Days 8-14, self-dosing compliance will be evaluated by pill count and subject 
report at each clinic visit.  Subjects will be instructed to call the physician’s office before 
taking the next dose of study medication if they notice any marked dizziness, especially 
when standing from a sitting or lying position.  The physician will determine if the next dose 
should be delayed, skipped, or the subject should be seen.  Any change in physician-
prescribed dosing will be noted in the study file and confirmed also by pill count and subject 
report at the next visit.
13.4 Nicotine Replacement Therapy
Subjects may be permitted to smoke during their participation in the Inpatient Treatment part 
of the study (Days 1-7) based on individual site policy.  If they usually use tobacco products, 
the study physician will offer and encourage these subjects to use nicotine replacement 
3 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval. 
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therapy (patch, gum, inhaler, or nasal spray) while they are in the hospital to treat their 
nicotine withdrawal symptoms.  If smoking is permitted by a participating site, smoking 
breaks outside of the inpatient locked unit must be constantly observed and supervised. The 
number of tobacco products used by subjects per day will be recorded in the subject’s source 
document and on the eCRF.
No control or record for use of tobacco products will be required during Days 8-14 of the 
study.
14 STUDY PROCEDURES
14.1 Subject Recruitment and Consent
Interested subjects, who respond to recruitment materials and are available to stay in the 
hospital for the 7-day Inpatient Treatment part of the study, will be scheduled to meet with a 
qualified investigative staff member and receive an explanation of the study purpose and 
requirements in lay language.  During the initial interview, the interviewer should not ask 
questions in a manner that reveals the eligibility criteria for study entry.
If still interested after receiving an explanation of the study, subjects will be given an 
opportunity to review, inquire about, and sign the study informed consent form (see     
Section 16.4). The subject will then be given a copy of the signed consent form. After that, 
subjects will be given a screening number and proceed to the screening phase of the study.  
Screening assessments must be completed within a 7-day time period, but can be completed 
as early as screening day 1, and randomization may be performed on the next calendar clinic 
visit day.  Subjects must be randomized no later than the 7th day of screening (Day 1). At no 
time during the screening process should individuals be given information regarding inclusion 
or exclusion criteria, with the exception that subjects will be informed that they must exhibit 
signs of opioid withdrawal immediately before admission into the study. When individuals 
are evaluated, questions should be asked in a way that the criteria are not discernible.
Any subject who has difficulty understanding the information contained in the consent form 
will reread the misunderstood portion(s) of the consent and discuss with a research staff 
member until s/he shows complete understanding of the information in the consent form, and 
may thus give full consent.  Subjects must complete a consent quiz with 100% accuracy 
before being randomized.  Research staff will work closely with the subject in an effort to 
help them understand the requirements of their participation. Subjects with literacy problems 
will be assisted to the extent possible.
Any subject who is unable to demonstrate understanding of the information contained in the 
informed consent will be excluded from study participation and assisted in finding other 
sources of treatment at the subject’s sole expense.  Subjects who are excluded, or who decline 
participation, may not be rescreened at a later time and will be given referrals to other 
resources in the area.  Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice.
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14.2 Screening
Screening assessments will be conducted as shown in Table 1 (Section 15).  The screening 
period will last up to 7 days during which the subjects must satisfy the eligibility criteria and 
complete all required screening assessments.
14.3 Treatment Phase
14.3.1 
Baseline
After a potential participant has completed all screening assessments and has met all 
eligibility criteria to participate in the study, the Site Investigator or study coordinator will 
arrange for an early morning hospital study admission (Day 1).  The Baseline period is the 
morning of Day 1 after the subject has completed final eligibility testing 
(OOWS-Handelsman) and has been admitted to the inpatient study unit, but before 
randomization. Baseline assessments to be done are shown in Table 1 and explained in 
Section 15.2. Subjects will be admitted to the study, will complete all Baseline measures, 
and will be randomized.  The Site Investigator or study coordinator will have the 
investigational agent dispensed and ready to administer, before the Day 1 8 AM dosing 
window.
14.3.2 
Subject Randomization
A prospective subject who meets all of the study inclusion criteria and does not meet any of 
the exclusion criteria may be randomized into the study.
A stratified randomization procedure will be used to separately allocate male and female 
subjects in 1 of the 3 treatment groups: 2.4 mg lofexidine, 3.2 mg lofexidine, or placebo.  
Randomization will be implemented centrally, that is, take place across all investigational 
sites using an Interactive Voice Response System (IVRS) or an Interactive Web Response 
System (IWRS) managed by the CRO 
  At randomization, the 
system will assign a unique subject identification number to each subject.  The subject’s 
identification number will be used on all of that subject’s case report forms.
The Site Investigator or study coordinator will arrange for hospital admission (in the event 
that the subject was not admitted the night before randomization) of the subject and for 
investigational agent to be dispensed to initiate treatment.  Even if a subject does not actually 
receive any investigational agent after s/he has been randomized, s/he is considered to be in 
the intent-to-treat (ITT) population.  
 should be notified of any 
irregularities that occur during randomization.
14.3.3 
Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment)
After randomization, subjects will receive their first dose of study medication (lofexidine or 
placebo) during the 8 AM dosing window on Day 1.  Subjects will be dosed 4 times daily 
from Day 1 through Day 7 at 8 AM, 1 PM, 6 PM, and 11 PM.  Vital signs will be recorded 
within 30 minutes before every dose and 3.5 hours after the 8 AM, 1 PM, and 6 PM dose. 
Other clinical assessments will be gathered between 11:00 AM and noon each day.  These 
clinical assessments are described in detail in Sections 15.4 and 15.5.
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14.3.4 
Days 8-14 (Open-Label, Continuation Treatment)
Subjects who successfully meet the definition for “completer” based on Days 1-7
(i.e., receives at least one dose of study medication on Day 7 and completes the 3.5-hour 
post-dose SOWS-Gossop assessment on Day 7) and if clinically indicated (as determined by 
the Site Investigator) may continue to receive lofexidine to control symptoms for up to an 
additional 7 days during Days 8-14. Subjects may be treated as inpatients or outpatients, 
depending on the wishes of the investigator and the subject, using open-label, variable dose 
lofexidine (as determined by the Site Investigator, but not to exceed 3.2 mg/day). The 
rationale for the decision to continue treatment or not and the Site Investigator’s decision to 
continue treatment through either an inpatient or outpatient setting must be documented in 
the subject’s source document. Lofexidine treatment will terminate and the subject will be 
discharged from the study when the Site Investigator judges that the acute phase of opioid 
withdrawal is essentially complete and the subject no longer needs treatment for abstinence.  
In any event, no subject will continue to receive lofexidine treatment for more than 14 days 
total from the onset of abstinence. If being treated as an outpatient, the subject must return to 
the clinic daily for assessment (see a complete list of assessments in Table 1 of Section 15).
14.3.5 
Maintaining and Breaking the Blind
In circumstances where breaking of the blind is necessary for subject safety, Investigators or 
emergent care professionals requesting to break the blind must call the Sponsor’s Medical 
Monitor (or designee) for consultation before unblinding unless immediate action is required. 
The decision to break the study blind should be resorted to only in cases of life-threatening 
emergency when knowledge of the treatment arm investigational agent will influence clinical 
management.
Contact information for the Sponsor’s Medical Monitor is as follows:
If, after discussion with the Medical Monitor, it is determined that the study treatment should 
be disclosed, medical personnel will be able to access this information via IVRS/IWRS.  
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 following information must be recorded in the subject’s record:  the reason for 
unblinding the code, the person who has unblinded the code, and the date and time of 
unblinding.
14.4 Subject Reimbursement
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14.5 Study Termination
14.5.1 
Subject Termination
A subject can withdraw his/her consent for participation in the study at any time without 
prejudice.  The Site Investigator may terminate a subject if s/he deems it clinically 
appropriate for any reason. Additionally, the Site Investigator must terminate a subject for 
any of the following reasons:
1. Cardiovascular events (see Section 14.5.2).
2. Serious medical problem thought to be related or unrelated to the study medications.
3. Intercurrent illness or medical complications that, in the opinion of the site investigator, 
preclude safe administration of study medications.
4. Evidence of illicit drug use while participating in the study.
5. Alcohol or other sedative/hypnotic withdrawal signs and symptoms developing following 
enrollment into the study.
6. Requiring therapy with an exclusionary drug.
7. Lack of compliance with protocol and/or unit procedures.
8. During Days 1-7, missing more than 2 doses of study medication in a single 24-hour 
period or missing more than 6 doses of study medication over the course of the inpatient 
treatment phase. 
Subjects who are removed from study treatment because of adverse events (AEs) or serious 
adverse (SAEs) will be followed until they are medically stabilized to the satisfaction of the 
attending physician (see Sections 15.5.1, 16.7, and 16.8). Appropriate safety evaluations 
will continue to be collected until the subject is discharged from the treatment center or the 
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maximum 14-day treatment period has expired.  This stabilization can include medically 
supervised opioid withdrawal (involving behavioral therapy, rescue opioid medications, 
and/or non-opioid pharmacotherapy) or referral to an appropriate methadone or 
buprenorphine therapy program.
Any subject that discontinues prematurely, regardless of the reason, will be requested to 
complete all assessments and procedures scheduled for Day 14 (see Table 1).
The reason for premature removal will be recorded in the subject’s source document and on 
the termination form provided in the subject’s eCRF. Once withdrawn, subjects may not re-
enter the study.  Similarly, the Site Investigator’s assessment of completion of 
detoxification/transition will also be recorded in the subject’s source document and on the 
eCRF. Withdrawn or early-completer subjects will not be replaced.
Study subjects withdrawn from the protocol secondary to a medical or psychiatric concern 
deemed to be unrelated to lofexidine therapy will be referred, at the subject’s sole expense, 
for appropriate treatment, and may include psychological and lifestyle counseling, support 
groups, pharmacological, and medical treatment.  Subjects will be asked to sign a general 
consent for the release of information to the referred healthcare provider. Study staff may 
request transportation for emergency treatment of a subject if medically appropriate (e.g., for 
acutely psychotic or suicidal subjects).
14.5.2 
Cardiovascular Events Requiring Subject Termination From Study
Subjects should be discontinued from the study for any of the reasons listed below, and the 
event should be recorded in the subject’s document and on the eCRF as an AE or SAE (see 
Sections 15.5.1, 16.7, and 16.8) and the subject followed until medically stabilized to the 
satisfaction of the attending physician.
1. New onset of clinically significant abnormal ECG (e.g., second or third degree heart
block or uncontrolled arrhythmia, prolonged QTcF interval4).
2. Persistent symptomatic hypotension (e.g., hypotension not responding to bed rest or
fluids).
3. 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.
4. Persistent hypertension – blood pressure ≥185/110 mmHg recorded on 3 separate 
occasions taken at least 5 minutes apart AND within a 1-hour time period.  If all 3
readings are ≥185/110 mmHg (either systolic ≥185 mmHg or diastolic ≥110 mmHg)
the subject must be terminated.
5. Medical Intervention for Cardiovascular Event:  Any medical intervention
(nonmedication or medication inclusive) used for the treatment of any cardiovascular
event, with the exception of a positional intervention in subjects displaying hypotension.
4 See Section 15.5.3 for procedures for assessment of prolonged QTcF interval.
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6. Any other clinically significant cardiovascular signs or symptoms that would place the
subject at risk.
14.5.3 
Trial Discontinuation
The Sponsor (USWM) has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following:
x
the incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects;
x
subject enrollment is unsatisfactory; and
x
data recording is inaccurate or incomplete.
14.6 Concomitant Therapy
The concomitant medications listed below are permitted during Days 1-7 and Days 8-14 
of the study.
1. Multivitamins (≤1 tablet orally, administered daily at 9 AM).
2. Guaifenesin (for cough) (≤2 teaspoons orally every 2 hours, as needed [PRN]).
3. Alumina, Magnesia, and Simethicone (for emesis and nausea) (≤30 mL orally every
4 hours, PRN).
4. Dioctyl sodium sulfosuccinate (for constipation) (≤100 mg orally every 8 hours, PRN).
5. Psyllium hydrocolloid suspension (for constipation) (≤1 tablespoon orally every
12 hours, PRN).
6. Bismuth sulfate (Pepto-Bismol®) (for diarrhea) (≤6 doses of 30 mL orally every
24 hours, PRN).
7. Acetaminophen (for headache, muscle aches, or other discomfort) (≤4 doses of ≤650 mg
orally every 24 hours).
8. Zolpidem (for insomnia) (≤10 mg orally, PRN, may repeat 1 time if administered before
5:00 AM (i.e., 3 hours before the first morning dose of lofexidine or placebo).  Zolpidem
must not be administered before 11:00 PM (which is the time of the last daily dose of
lofexidine or placebo).
8a. Note:  A short-acting benzodiazepine (e.g., oxazepam) may be used ad libitum for
insomnia during the second part of the study (i.e., Days 8-14).
9. Nicotine replacement therapy (patch, inhaler, gum, nasal spray).
All other medications must be approved by the Sponsor’s Medical Monitor before 
administration.  If a subject requires any other medication for intolerable nausea and emesis 
(including a prescription opioid or non-opioid or an over-the-counter opioid or non-opioid) 
other than alumina, magnesia and simethicone, the subject will be withdrawn from the study 
and given appropriate treatment according to the standard of care (see Section 14.5.1).
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All medications taken will be recorded in the subject’s source document and eCRF along 
with dose, dates of administration, and reason for use.
15 CLINICAL EVALUATIONS
A detailed Schedule of Assessments to be done in the study is provided in Table 1.
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Table 1.
Schedule of Study Assessments
Randomized, Double-Blind, Placebo-Controlled (Days 1-7) followed by 
Open-Label, Continuation Treatment (Days 8-14)
Screening
Baseline (a)
Inpatient
Treatment
In/Outpatient
Treatment
Activity
Day:
-6 to -1
1
1-7
8 to 14/ET*
Informed Consent Signed
X
Screening Number Assigned
X
Inclusion/Exclusion Criteria
X
X (b)
Prior Medication History
X
X (b)
Demographics
X
Medical and Smoking History
X
Mini-International Neuropsychiatric Interview
X
Infectious Disease Assessments (c)
X
Pregnancy Test (d)
X
X
Day 14/ET
Height
X
Weight
X
Day 14/ET
Admission to Inpatient Unit
X
Randomization
X
Study Medication Administration
X (QID)
X (variable)
Medication Compliance
X
X
Discharge from Inpatient Unit
Day 7
Efficacy Assessments
Short Opiate Withdrawal Scale of Gossop (e)
X
X
X
Objective Opiate Withdrawal Scale of Handelsman (e)
X
X (f)
X
X
Modified Clinical Global Impression (e)
X
X
Visual Analog Scale for Efficacy (e)
X
X
Clinical Opiate Withdrawal Scale (e)
X
X
X
X
Concomitant Medications Assessment
X
X
Assessment of Detoxification Completion
X (g)
X
30-Day Post Discharge Phone Follow Up (h)
X
Safety Assessments
Adverse Events Assessment
X
X
Vital Signs (Sitting & Standing)
X
X
X (i)
X (j)
12-Lead Electrocardiogram (duplicate)
X (k)
X (l)
X (m)
Pharmacokinetic Sampling
X (n)
Clinical Laboratory Tests (hematology, chemistry, urinalysis)
X
X (o)
X (o)
Physical Exam (p)
X
X
X
X
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Table 1.
Schedule of Study Assessments
Randomized, Double-Blind, Placebo-Controlled (Days 1-7) followed by 
Open-Label, Continuation Treatment (Days 8-14)
Screening
Baseline (a)
Inpatient
Treatment
In/Outpatient
Treatment
Activity
Day:
-6 to -1
1
1-7
8 to 14/ET*
Urine Drug Screen (q)
X
X
X
X
30-Day Post Discharge Phone Follow Up (h)
X
Abbreviations: ET = Early Termination, QID = 4 times daily
* Day 14 or and End of Study/Early Termination (ET) assessment, as applicable.
(a)
The Baseline period is the morning of admission, before randomization.
(b) This form is to be updated at Baseline.
(c)
A chest x-ray is required only if a PPD (purified protein derivative) skin test for tuberculosis is not done, the current PPD is positive, or if a past PPD was positive.
(d) The urine sample collected on the first day of screening will be divided into two aliquots.  One sample will be sent to the central lab 
for
urinalysis and the other sample will be used for urine drug screening and immediate “dipstick” analysis of pregnancy (females only).
(e)
During Inpatient Treatment (Days 1-7), efficacy scales will be completed daily: the Short Opiate Withdrawal Scale of Gossop 3.5 hours (±10 minutes) after the first dose of 
study medication followed by the other efficacy scales shortly thereafter.  Efficacy scales will be completed daily before dosing during Days 8-14.
(f)
The Objective Opiate Withdrawal Scale of Handelsman (OOWS-Handelsman) will be completed at Baseline to determine final eligibility as subjects must have a score ≥2 in 
order to participate in the study (inclusion criterion #4).
(g) To be done at discharge from the Inpatient Treatment part of the study or early withdrawal (Days 1-7), and each day during Days 8-14 or, if applicable, early 
termination/discharge from Days 8-14.
(h) The 30-day post discharge follow-up telephone contact will include an evaluation of the subject’s current treatment status (e.g., relapse, current psychosocial treatment, 
successful entry into a methadone, buprenorphine, or naltrexone program) and an adverse event evaluation.
(i)
Vital signs (sitting/standing blood pressure and pulse) will be measured before every dose and 3.5 hours after study medication administration at 8 AM, 1 PM, and 6 PM 
(7 times per day).
(j)
Vital signs (sitting/standing blood pressure and pulse) will be measured at least once daily before dosing and 3.5 hours after dosing. Note that if subjects are being treated on 
an outpatient basis and cannot stay in the clinic for measurement of the 3.5-hour post-dose vital signs, they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point.  They will also be provided a diary to record the measurements.
(k) Baseline 12-lead electrocardiograms (ECGs) will be done on one day during the screening period, time-matched to the post randomization ECG schedule (i.e., pre-1 PM 
[before 1 PM dose], 4 PM [3 hours post-dose], and 5 PM [4 hours post-dose]).
(l)
12-lead ECGs will be done before the first daily dose, pre-1 PM dose, at 4 PM, and at 5 PM on Days 1 and 7; before the first daily dose only on Days 2 and 4; and, if 
applicable, at early termination from Days 1-7.
(m) 12-lead ECGs will be done before the first daily dose and 3.5 hours after first daily dose on Days 8 and 14 or, if applicable, at early termination/discharge during Days 8-14.
(n) A finger prick blood sample will be collected concurrently with each scheduled ECG during Days 1-7 only.
(o) Clinical lab testing will be done as clinically warranted, at discharge from the Inpatient Treatment part of the study or early termination (Days 1-7), and on Day 14 or, if 
applicable, early termination/discharge from Days 8-14.
(p) A complete physical examination will be performed during screening and the physical exam form will be updated at Baseline.  A complete physical examination will be 
performed on Day 1 (3-4 hours after randomization) and at discharge or early termination from the Inpatient Treatment phase (Days 1-7).  During Days 8-14, a complete 
physical exam will be performed as clinically warranted and on Day 14 or, if applicable, early discharge/termination from the study.
(q) Urine drug screen will be done at least every other day to monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
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15.1 Screening Assessments
Subjects seeking treatment for opioid dependence at one of the study sites will be screened 
for study enrollment.  Screening assessments must be completed within a 7-day time period.  
Subjects cannot be admitted later than the morning of the 7th day of the screening period.  
Written informed consent must be obtained from all study subjects before initiation of any 
study procedures.
The following screening assessments must be completed during screening after written 
informed consent is obtained:  height; weight; vital signs; blood collection for standard 
clinical safety laboratory assessments (including hematology and biochemistry); urine 
sample for confirmatory drug testing, urinalysis, and pregnancy assessment (if female); and 
infectious disease assessment (see Section 15.5.4.2) and a chest x-ray if a past PPD skin test 
for tuberculosis was positive.
The urine sample collected will be divided into two aliquots. One sample will go to the 
central lab 
for urinalysis; the other sample will be used 
for “dipstick” analysis of pregnancy and qualitative drug screening.
The assessments listed below must also be performed during screening.
x
12-lead ECG (in duplicate) will be done on one day during the screening period,
time-matched to the post randomization ECG schedule, i.e., pre-1 PM (before 1 PM 
dose), 4 PM (3 hours post-dose), and 5 PM (4 hours post-dose).
x
Medical and smoking/alcohol history.
x
Complete physical examination.
x
Mini International Neuropsychiatric Interview (M.I.N.I.) [17, 18]. The M.I.N.I will 
be performed once at screening only to (1) establish that each potential subject is
opioid-dependent (inclusion criterion #2), (2) exclude other drug dependency 
(exclusion criterion #4), and (3) determine the absence of major psychiatric disorders 
(exclusion criterion #9).
x
Prior medications will be recorded to capture all medications taken in the past 
30 days.
x
OOWS-Handelsman.
x
Clinical Opiate Withdrawal Scale (COWS).
15.2 Baseline Assessments
The Baseline period is the morning of admission to the study, before randomization and 
dosing.  Prospective subjects who meet all eligibility criteria must be admitted to the study in 
time to give the first dose of study medication at 8 AM.
The assessments listed below will be performed during the Baseline period.
x
OOWS-Handelsman (score must be ≥2 for randomization).
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x
SOWS-Gossop.
x
COWS.
x
Vital signs (sitting/standing blood pressure and pulse) measurements.
x
Repeat pregnancy assessment (by “dipstick”), if female.
x
Repeat urine drug screen (by “dipstick”).
x
Update Inclusion/Exclusion Criteria form to reflect Baseline assessments.
x
Update prior medication form and physical examination form to capture any new 
medications and/or medical problems since screening.
15.3 Assessments During Treatment
15.3.1 Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment) 
The assessments listed below will be performed daily (unless otherwise specified) on 
Days 1-7.
x
Efficacy assessments at estimated time of maximum plasma concentration (Tmax,
i.e., 3.5 hours after the first daily dose) including:
¾ SOWS-Gossop;
¾ OOWS-Handelsman;
¾ Modified Clinical Global Impressions Scale (MCGI) (Subject and Rater);
¾ Visual Analog Scale for Efficacy (VAS-E); and
¾ COWS.
x
Concomitant medication assessment.
x
Completion of detoxification as assessed by the Site Investigator (after completion of 
the SOWS-Gossop and other efficacy scales) at completion of Inpatient Treatment on 
Day 7 only or, if applicable, early termination during Days 1-7).
x
Vital signs (sitting/standing blood pressure and pulse) before every dose and 
3.5 hours after the 8 AM, 1 PM, and 6 PM dose (7 times per day).
x
Continuous monitoring for AEs.
x
12-lead ECGs (in duplicate) will be done before the first daily dose, pre-1 PM dose,
at 4 PM, and at 5 PM on Days 1 and 7; before the first daily dose only on Days 2 and 
4; and, if applicable, early termination during Days 1-7.
x
Complete physical examination 3 to 4 hours after randomization on Day 1 and at 
discharge or, if applicable, early termination during Days 1-7.
x
Finger prick blood sample for pharmacokinetic (PK) analysis will be collected 
concurrently with each scheduled ECG during Days 1-7.
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x
Clinical laboratory tests as clinically warranted and at discharge or, if applicable, 
early termination during Days 1-7.
x
Pregnancy test at early termination during Days 1-7.
In addition, qualitative urine drug screening (by on-site use of “dipsticks”) will be done at 
least every other day to monitor for contraband.
15.3.2 
Days 8-14 (Open-Label, Continuation Treatment) The 
assessments listed below will be performed daily on Days 8-14.
x
Efficacy assessments before dosing including:
¾ SOWS-Gossop;
¾ OOWS-Handelsman;
¾ MCGI (Subject and Rater);
¾ VAS-E; and
¾ COWS.
x
Concomitant medication assessment.
x
Completion of detoxification as assessed by the Site Investigator daily on Days 8-14
and/or on early discharge/termination.
x
Pill count to measure compliance with previous day’s doses.
x
Vital signs (sitting/standing blood pressure and pulse) at least once daily before 
dosing and 3.5 hours after dosing. Note that if subjects are being treated on an 
outpatient basis and cannot stay in the clinic for measurement of the 3.5-hour post-
dose vital signs, they will be given a portable digital blood pressure machine for 
measurement of their vital signs at this required time point.  They will also be 
provided a diary (Appendix 8) to record the measurements.
x
AE assessment.
x
12-lead ECGs (in duplicate) will be done before the first daily dose and 3.5 hours 
after the first daily dose on Days 8 and 14 or, if applicable, early 
discharge/termination during Days 8-14.
x
Clinical laboratory tests as clinically warranted and on Day 14 or, if applicable, early 
discharge/termination during Days 8-14.
x
Complete physical examination as clinically warranted and on Day 14 or, if 
applicable, early discharge/termination during Days 8-14.
x
Pregnancy test on Day 14 or, if applicable, early discharge/termination during 
Days 8-14.
Qualitative urine drug screening (by on-site use of “dipsticks”) will be done at least every 
other day to monitor for contraband (inpatient setting) or illicit (outpatient setting) drug use.
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A 30-day post discharge follow-up telephone contact will be made for an adverse event 
evaluation and an evaluation of the subject’s current treatment status (e.g., relapse, current 
psychosocial treatment, successful entry into a methadone, buprenorphine, or naltrexone 
program).
15.4 Efficacy Assessment Methods
15.4.1 
Short Opiate Withdrawal Scale (SOWS-Gossop)
The SOWS-Gossop [16] will be completed by the subject at baseline (before randomization), 
once daily at 3.5 hours (± 10 minutes) after the first dose of study medication on Days 1-7, 
and once daily before dosing on Days 8-14. Note that at the time of each daily evaluation, 
subjects should consider their symptoms over the last 24-hour period.  Also, this scale should 
be completed before completion of the OOWS-Handelsman, MCGI, VAS-E, and COWS.
The SOWS-Gossop scale assesses subjective symptoms of opioid withdrawal (Appendix 1). 
It is a subject-rated scale consisting of 10 items that are scored on a 4-point scale of 0 = none, 
1 = mild, 2 = moderate, and 3 = severe (minimum score of 0, maximum score of 30) (see 
Table 2 below).  The overall score will be the simple sum of the 10-item scores. Lower 
observed values in SOWS-Gossop scores indicate a more positive clinical outcome.
Table 2. 
SOWS-Gossop Scoring Method
Condition
Score
None
Mild
Moderate
Severe
Feeling Sick
0
1
2
3
Stomach Cramps
0
1
2
3
Muscle Spasms/Twitching
0
1
2
3
Feeling of Coldness
0
1
2
3
Heart Pounding
0
1
2
3
Muscular Tension
0
1
2
3
Aches and Pains
0
1
2
3
Yawning
0
1
2
3
Runny Eyes
0
1
2
3
Insomnia/Problems Sleeping
0
1
2
3
Note:  Possible score range = 0 to 30.
15.4.2 
Objective Opiate Withdrawal Scale (OOWS-Handelsman)
The OOWS-Handelsman [19] will be performed by a trained observer during screening, 
twice on Day 1 (during Baseline to confirm final eligibility for randomization [score of ≥2 is  
required per inclusion criterion #4] and 3.5 hours after the first dose of study medication, 
after completion of the SOWS-Gossop), once daily at 3.5 hours after the first dose of study 
medication on Days 2-7 (after completion of the SOWS-Gossop), and once daily before 
dosing on Days 8-14 (after completion of the SOWS-Gossop).
The subject will be observed for 5 minutes, and the presence or absence of 13 physical signs 
of opioid withdrawal will be recorded (Appendix 2). The presence of a sign will be assigned 
1 point, yielding a possible total score ranging from 0 to 13 (see Table 3 below). Lower 
observed values in OOWS-Handelsman scores indicate a more positive clinical outcome.
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Ambient room temperature will be recorded on the eCRF for all OOWS-Handelsman
observations.
Table 3. 
OOWS-Handelsman Scoring Method
Symptom (a)
Score (b)
0
1
Yawning( Frequency = # of yawns per observation period)
None
≥1
Rhinorrhea( Frequency = # of sniffs per observation period)
0-2
≥3
Piloerection (Gooseflesh - observe subject’s arm)
None
Present
Perspiration
None
Present
Lacrimation
None
Present
Mydriasis
None
Present
Tremors (hands)
None
Present
Hot and Cold Flashes (shivering or huddling for warmth)
None
Present
Restlessness (frequent shifts in position)
None
Present
Vomiting (c)
None
Any
Muscle Twitches
None
Any
Abdominal Cramps (holding stomach)
None
Present
Anxiety (d)
None
Mild, Moderate or Severe
(a) Observed over a 5-minute period.
(b) For total score: Minimum = 0; Maximum = 13.
(c) Present during 5-minute observation period.
(d) Mild = observable manifestations, such as foot shaking, fidgeting, finger tapping.
Moderate to severe = agitation, unable to sit, trembling, panicky, complains of difficulty in breathing, choking
sensations, palpitations.
15.4.3 
Modified Clinical Global Impressions Scale (MCGI)
The Clinical Global Impressions rating scale (1985) was developed by the National Institute 
of Mental Health (NIMH), and originally contained 3 questions.  For this study, Questions #1 
and #3 have been modified from the original scale, and Question #2 was not included
(Appendix 3).
In the original scale, Question #1 (severity of illness) evaluates the subject using a severity 
scale from 0 (not assessed), 1 (normal, not at all ill) to 7 (among the most extremely ill 
subjects).  The language of this question has been modified in this study for the subject 
assessment to make the scale more appropriate to opioid withdrawal.  The original 
Question #2 referred to “global improvement” and is omitted from this study, since all 
subjects will be treated, and there is no untreated screen withdrawal.  Question #3 (efficacy 
index) records responses on a factorial grid – side effects on one side and therapeutic effects 
on the other side.  Since there is no untreated screen withdrawal data, the therapeutic effect 
cannot be assessed; therefore, only the side effect responses will be examined.
The MCGI scale is used to estimate the overall clinical benefit of lofexidine treatment.  The 
MCGI will be completed once daily at 3.5 hours after the first dose of study medication on 
Days 1-7 (after completion of the SOWS-Gossop), and once daily before dosing on
Days 8-14 (after completion of the SOWS-Gossop). The modified subject and observer 
scales used in this study are presented below in Table 4. Lower observed values in MCGI 
scores indicate a more positive clinical outcome.
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Table 4.
MCGI Scoring Method
MCGI
Score
1
2
3
4
5
6
7
Subject Scale
Severity of Opiate 
Withdrawal
Symptoms (a)
None
Between 
none and 
mild
Mild
Moderate
Marked
Severe
Most 
severe I 
ever had
Side Effects (b)
None
Slight, does 
not 
significantly
interfere with 
daily 
activities
Moderate, 
significantly 
interferes 
with daily 
activities
Severe, 
greater than 
symptom 
relief
Observer Scale
Severity of 
Illness (a)
Not at 
all ill
Borderline ill
Mildly ill
Moderately 
ill
Markedly 
ill
Severely 
ill
Among the 
most 
extremely 
ill subjects
Side Effects (b)
None
Does not 
significantly 
interfere with 
subject’s 
functioning
Significantly 
interferes 
with 
subject’s 
functioning
Out-weighs 
therapeutic 
effect
(a) Maximum score of 7.
(b) Maximum score of 4.
15.4.4 
Visual Analog Scale for Efficacy (VAS-E)
The effectiveness of lofexidine in alleviation of withdrawal sickness will be assessed by 
subjects using the VAS-E, which will be completed once daily on Days 1-7, 3.5 hours after 
the first dose of study medication (after completion of the SOWS-Gossop) and once daily 
before dosing on Days 8-14 (after completion of the SOWS-Gossop).  Subjects will make a 
mark on a 100-mm VAS scale to reflect the effectiveness of lofexidine in relieving 
withdrawal sickness from Not Effective at all (0 mm) to Completely Effective (100 mm). 
Greater observed values in VAS-E scores indicate a more positive clinical outcome
(Appendix 4).
15.4.5 
Clinical Opiate Withdrawal Scale (COWS)
The COWS [20] will be used to assess the effectiveness of lofexidine in alleviation of opioid 
withdrawal, and will be completed during screening, at baseline (before randomization), once 
daily at 3.5 hours after the first dose of study medication on Days 1-7 (after completion of the 
SOWS-Gossop), and once daily before dosing on Days 8-14 (after completion of the 
SOWS-Gossop).  The COWS is a clinician-administered instrument that rates 11 common 
opioid withdrawal signs and symptoms (Appendix 5).  These include:  resting pulse rate; 
sweating; restlessness; pupil size; bone or joint aches; runny nose or tearing; gastrointestinal 
(GI) upset; tremor; yawning; anxiety or irritability; and gooseflesh skin.  The score for each 
item reflects the severity of the sign or symptom, and the total scores are grouped as mild 
(5-12 points), moderate (13-24 points), moderately severe (25-36 points), and severe (>36 
points).
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15.4.6 
Assessment of Completion of Detoxification
At the completion of Inpatient Treatment on Day 7 or, if applicable at early termination from 
Days 1-7, the Site Investigator will indicate if the subject has completed detoxification and 
can be discharged without further lofexidine treatment. The same assessment will be made at 
each visit during Days 8-14.
15.4.7 
Concomitant Medication Use
Multivitamins, nicotine replacement therapy, and several other concomitant medications for 
minor complaints (e.g., diarrhea, constipation, mild nausea, headache, muscle aches, cough, 
insomnia) will be allowed during the study.  All concomitant medications administered will 
be recorded daily.
15.4.8 
Withdrawal-Related Adverse Events
The Site Investigator will indicate, using his/her best judgment, whether any adverse event 
that occurs during the study is secondary to opioid withdrawal. Individual items reported on 
the efficacy scales (i.e., SOWS-Gossop, OOWS-Handelsman) do not automatically qualify as 
a withdrawal-related AE unless the subject specifically reports them in response to a non-
leading question (i.e., “How have you been feeling since I saw you last?”).  In the event a 
subject reports “withdrawal” or a similar event encompassing a collection of potential 
withdrawal symptoms, the subject should be asked to elaborate so that specific symptoms can 
be recorded on the AE eCRF. In this case, the AEs recorded should include both the original 
reported condition (e.g., “withdrawal syndrome”) as well as the individual symptoms that the 
subject lists after further inquiry (e.g., anxiety, upset stomach).
15.4.9 
Subject Treatment Status 30 Days Post Discharge
A follow-up telephone contact will be made by the Site Investigator, including an evaluation 
of the subject’s current treatment status (e.g., relapse, current psychosocial treatment, 
successful entry into a methadone, buprenorphine, or naltrexone program) and an adverse 
event evaluation.
15.5 Safety Assessment Methods
15.5.1 
Adverse Events
Adverse events will be assessed and recorded around the same time each day by study staff 
during Days 1-7. If an AE requires medical attention, it should be reported to a study 
physician immediately.  A study physician must meet with the subject to assess all medical 
and psychiatric AEs reported by the subject, as well as those recorded by other study staff. 
Adverse events will be assessed by asking the subject, “How have you been feeling since I 
saw you last?” After current AEs are assessed, the study physician must review with the 
subject and assess any AEs unresolved from the previous day.  After each daily AE 
assessment, the physician will record in the subject’s source document and AE eCRF, 
according to the procedures described in Section 16.7, the type of AE and whether serious 
(SAE) or non-serious, severity of each AE, and the relationship to the study agent. These 
categories are asking for the physician’s best judgment of the severity and relatedness of 
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each AE. The physician will also record, based on his/her best judgment, whether the AE is 
secondary to opioid withdrawal (see Section 15.4.8).  In general, an AE should not be marked 
as withdrawal related AND related to study medication.
Any study subject with a related AE will be followed by the attending physician until the 
event is resolved to the satisfaction of the Site Investigator and Sponsor’s Medical Monitor.  
If the AE is unrelated, the subject will not be discharged until medically stable, and then will 
be referred, at the subject’s sole expense, for ongoing care and/or treatment, which may 
include psychological and lifestyle counseling, support groups, or pharmacological and 
medical treatment.
During Days 8-14, in either an inpatient or outpatient setting, subjects will be queried about 
adverse events daily.  All subjects will be instructed to contact the treating physician if he or 
she feels dizzy (especially on standing from a sitting or lying position) and delay additional 
lofexidine dosing until instructed by the physician.  All reported AEs will be recorded as 
described above.
15.5.2 
Vital Signs
Vital signs (systolic and diastolic blood pressure, pulse) are to be measured at screening for 
all subjects.
During Days 1-7, vital signs (sitting/standing systolic and diastolic blood pressure, pulse) 
will be measured at Baseline and on Days 1-7, within 30 minutes before receipt of study 
medication at 8 AM, 1 PM, 6 PM, and 11 PM and 3.5 hours (±15 minutes) after receipt of 
study medication at 8 AM, 1 PM, and 6 PM.
During open-label treatment, in an inpatient or outpatient setting (Days 8-14), vital signs will 
be measured at least once daily before dosing and 3.5 hours (±30 minutes) after dosing. If 
subjects are being treated on an outpatient basis and cannot stay in the clinic for 
measurement of the 3.5-hour post-dose vital signs, they will be given a portable digital blood 
pressure machine for measurement of their vital signs at this required time point.  They will 
also be provided a diary (Appendix 8) to record the measurements.
For the orthostatic blood pressure readings, subjects will remain sitting for 3 minutes before a 
blood pressure reading, and then stand for 3 minutes before a second blood pressure reading 
is taken. If a subject demonstrates potentially clinically significant vital signs, as per any one 
of the criteria (i.e., systolic values, diastolic values, or pulse values meet the specified 
criteria) in the guidelines shown below, the event should be recorded in the subject’s source 
document and eCRF as an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) and the subject 
should be followed until medically stabilized to the satisfaction of the attending physician. 
Additional dose-hold and discontinuation criteria are provided in Sections 13.2.2 and 13.2.3, 
respectively.
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Vital Sign 
Parameter
Observed 
Value
Change Relative
to Screen
Systolic Blood
≥180 mmHg
A
N
D
Increase of ≥20 mmHg
Pressure
≤90 mmHg
Decrease of ≥20 mmHg
Diastolic Blood
≥105 mmHg
Increase of ≥15 mmHg
Pressure
≤50 mmHg
Decrease of ≥15 mmHg
Pulse
≥120 bpm
Increase of ≥15 bpm
≤50 bpm
Decrease of ≥15 bpm
Operational Note:  When a vital sign or QTcF reading meets any of the defined 
cut-off criteria for discontinuation, the values will be confirmed by repeating the 
measurement twice, approximately 10 to 15 minutes apart.  If 2 of the 3 total 
readings confirm that the subject meets discontinuation criteria, the subject will 
be terminated from the study.  If 2 of the 3 total readings are within acceptable 
limits (and they do not meet the other discontinuation criteria detailed in  
Section 14.5.2), the subject may continue in the study.
Additionally, when the subject is experiencing blood pressure- or pulse-related symptoms 
(e.g., lightheaded, dizziness, palpitations), these should be recorded in the subject’s source 
document and eCRF as an AE or SAE (see Sections 15.5.1, 16.7, and 16.8) even if the vital 
signs values do not meet the predefined criteria shown above.
15.5.3 
12-Lead Electrocardiograms
Using ECG core lab-provided and validated instruments, baseline paper tracing 12-lead ECG 
(in duplicate) will be conducted on one day during the screening period, time-matched 
(± 15 minutes) to the post randomization ECG schedule, i.e., pre-1 PM (before 1 PM dose), 
4 PM (3 hours post-dose), and 5 PM (4 hours post-dose). During Days 1-7, 12-lead ECGs (in 
duplicate) will be conducted before the first daily dose, pre-1 PM dose, at 4 PM, and at 5 PM 
on Days 1 and 7; before the first daily dose only on Days 2 and 4; and, if applicable, early 
termination during Days 1-7. During Days 8-14, 12-lead ECGs (in duplicate) will be 
conducted before the first daily dose and 3.5 hours after the first daily dose on Days 8 and 14 
or, if applicable, early termination/discharge during Days 8-14. ECG intervals and 
abnormalities will be read centrally by a computer and confirmed by an individual accredited 
to read ECGs at the ECG core lab 
A qualified physician on site will evaluate 
tracings if there is significant abnormality. The following intervals will be computed:
x
Ventricular Rate
Number of R waves appearing within a 6-second period, 
multiplied by 10;
x
PR Interval
Measured from the onset of the P wave to the onset of the QRS 
complex;
x
QRS Complex
Measured from the beginning of the down stroke of the Q wave 
to the completion of the upstroke of the S wave;
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x
QT Interval
x
QTc (Bazett)
x
QTc (Fridericia)
Measured from the beginning of the down stroke of the Q wave 
to the completion of the T wave;
QT interval corrected for heart rate using Bazett’s formula 
(QT/square root of RR) (for analysis purposes).
QT interval corrected for heart rate using Fridericia’s formula 
(QT/cube root of RR) (for safety monitoring/subject 
termination purposes).
At screening (baseline assessment), a QTcF interval greater 
than 450 msec for males and greater than 470 msec for females 
will exclude the subject from study participation (see exclusion 
criterion #6 in Section 11.2.2).  In such cases, 2 additional 
ECGs should be taken at 10- to 15-minute intervals.  The QTcF 
interval on all 3 ECGs should be confirmed by the Site 
Investigator and if 2 of the 3 QTcF intervals exceed the gender-
specific cut-off, then the subject should be judged a screen 
failure and not randomized to treatment.
During the treatment phase of the study, when any QTcF 
interval exceeds 495 msec, 2 additional ECGs should be taken 
at 10- to 15-minute intervals.  The QTcF interval on all 3 ECGs 
should be confirmed by the Site Investigator.  If it is 
determined that 2 of the 3 QTcF intervals exceed 500 msec or 
>25% above screen value, then the subject will be terminated
from the study.
Any time that 2 of the 3 QTcF measurements exceed 500 msec, 
contact the Sponsor’s Medical Safety Monitor,
 
to discuss the subject and the 
AE/SAE determination.
15.5.4 
Clinical Laboratory Evaluations
15.5.4.1 
Standard Laboratory Tests
Standard clinical laboratory safety evaluations (see Table 5) will be performed for all 
subjects at screening, as needed at the physician’s discretion throughout the study, at 
discharge from the Inpatient Treatment part of the study or early termination (Days 1-7), and 
on Day 14 or, if applicable, early discharge/termination during Days 8-14. For this 
multicenter study, a central laboratory 
 will be used that is 
directly accredited by the College of American Pathologists (CAP) and licensed by the 
Clinical Laboratory Improvement Act of 1988 (CLIA); both certification and accreditation 
must be renewed every 2 years.  The laboratory will need to provide a copy of current 
certification and provide the normal values for all analytes to determine the upper limit of 
normal (ULN).
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Table 5. Hematology, Chemistry, and Urinalysis Tests
Hematology (a)
Chemistry (b)
Urinalysis
Hemoglobin
Cholesterol
Specific gravity
Hematocrit
Triglycerides
pH
Red blood cell (RBC) count
Sodium
Bilirubin
White blood cell (WBC) count
Potassium
Urobilinogen
WBC differential (%)
Chloride
Glucose
neutrophils
Carbon dioxide (CO2)
Protein
lymphocytes
Glucose
Ketones
monocytes
Creatinine
WBC
eosinophils
Albumin
RBC
basophils
Total protein
Epithelial cells
Prothrombin time (PT)
Calcium
Partial thromboplastin time (PTT)
Phosphorus
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Gamma-glutamyl transpeptidase (GGT)
Total bilirubin
Lactate dehydrogenase (LDH)
Alkaline phosphatase
Blood urea nitrogen (BUN)
Thyroid-stimulating hormone (TSH)
Free thyroxine (T4)
(a) Blood will be collected in anticoagulant containing evacuated venous blood collection tubes 
(e.g., Vacutainer™).
(b) Blood will be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures.
15.5.4.2 
Infectious Disease Panel and Syphilis Tests
The infectious disease panel and syphilis tests will be assayed at screening only.  Blood will 
be collected in serum separation evacuated venous blood collection tubes 
(e.g., Vacutainer™) and serum separated according to standard procedures. Qualitative 
analysis reporting positive/negative results will be performed for the following analytes: 
Hepatitis B surface antigen (Hbs Ag), Hepatitis B surface antibody (anti-HBs), Hepatitis B
core antibody (anti-HBc), and Hepatitis C virus antibody (HCV Ab). A PPD skin test for 
tuberculosis and/or a chest x-ray will be performed on all subjects.  If the PPD is positive, a 
chest x-ray is required to assess active tuberculosis. If the subject reports that s/he has been 
previously positive for the PPD test, the PPD test will not be performed and only a chest 
x-ray will be required. A rapid plasma reagin (RPR) test for syphilis will be performed.  If 
positive, a confirmatory test (FTA-ABS or MHA-TP) will be performed.
If either PPD with chest x-ray, chest x-ray, or the confirmatory test for RPR is positive, 
subjects will not be eligible for study participation and will be referred, at subject’s sole 
expense, for appropriate follow-up and/or treatment.
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15.5.4.3 
Urine Toxicology Screening
Qualitative urine drug screening (UDS) will be performed at screening for all subjects, at 
Baseline, and at least every other day for the following drugs:  
amphetamines/methamphetamines, cocaine, barbiturates, opiates, benzodiazepines, 
cannabinoids, methadone, and buprenorphine. The central lab will provide standard sets of 
UDS “dipsticks” for use across all sites.
15.5.4.4 
Pregnancy Test
A “dipstick” pregnancy test designed to measure human chorionic gonadotropin will be 
performed on the first day of screening, at Baseline, and on Day 14 or early completion/early 
termination for all female subjects regardless of their childbearing capacity.  The central lab 
will provide study sites with a supply of pregnancy dipsticks.
15.5.4.5 
Pharmacokinetic Sampling
A finger prick blood sample will be collected concurrently with each scheduled ECG during 
Days 1-7 only.
15.5.5 
Physical Examination
A complete physical examination of the oral cavity, head, eyes, ears, nose and throat, 
cardiovascular system, lungs, abdomen (liver/spleen), extremities, skin, neuropsychiatric 
mental status and sensory/motor status, musculoskeletal system, and general appearance 
should be performed at screening for all subjects.
An update of the Physical Exam is required at Baseline (before randomization on Day 1) and 
then a complete physical examination should be performed 3 to 4 hours after randomization
on Day 1 and at discharge or early termination from Days 1-7. For Days 8-14, a complete 
physical examination should be performed as clinically warranted and on Day 14 or, if 
applicable, early discharge/termination from the study.
Height should be recorded at screening only.
15.6 Other Assessments
15.6.1 
Prior Medications
All medications taken by the subject for the 30 days before screening and during the 
screening period will be recorded in the subject’s source document and on the Prior 
Medication eCRF.  Prior medication usage should be updated at Baseline.  The reported 
medications will be reviewed and approved by the Site Investigator/study physician for entry 
into the study.
15.6.2 
Concomitant Medication Administration
Concomitant medication administration will be recorded daily. All concomitant medications 
should be recorded in the subject’s source document and on the Concomitant Medication 
eCRF.  All medications taken by the subject during study participation that are not on the list 
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of permitted concomitant medications (see Section 14.6) must be pre-approved by the Site 
Investigator/study physician with concurrence of the Sponsor’s Medical Monitor and 
recorded on the concomitant medication administration form.
16 REGULATORY AND REPORTING REQUIREMENTS
16.1 Good Clinical Practices
This study will be conducted in accordance with the most current version of the International 
Conference on Harmonization (ICH) Guideline for Good Clinical Practices (GCP).  An 
Operations Manual will be provided to all investigational sites as a study quality assurance 
tool.  The monitoring of the sites participating in the trial will be executed according to GCP 
guidelines.  Monitors will examine subjects’ study files including source documents in both 
the clinic files and subjects’ official medical records, and will also review 
regulatory/essential documents such as correspondence with the IRB and the Sponsor 
(USWM).  Areas of particular concern will be subject informed consent issues, protocol 
adherence, safety monitoring, IRB reviews and approvals, safety reports/regulatory forms, 
subject records, study drug accountability, and principal investigator supervision and 
involvement in the trial.  Reports will be prepared following each visit and forwarded to the 
Sponsor’s Clinical Project Manager.  Monitors will also prepare follow-up letters detailing 
their findings and any items requiring further resolution or attention by the site.  Follow-up 
letters will be provided to the Site Investigator, site coordinator, and Sponsor’s Clinical 
Project Manager.
16.2 FDA Form 1572 and Financial Disclosure
The Site Investigator will sign a Statement of Investigator (FDA Form 1572) before initiating 
this study. The names of any sub-investigators must appear on this form.
The Site Investigator and any sub-investigators will also sign a Financial Disclosure form 
before initiating this study.
16.3 Institutional Review Board Approval
Before initiating the study, Site Investigator will obtain written IRB approval to conduct the 
study.  No study medication will be shipped until IRB approval is obtained.  Should changes 
to the study protocol become necessary, protocol amendments (provided by the Sponsor) will 
be submitted in writing to the central IRB 
 and the Site Investigator’s IRB for IRB 
approval before implementation. In addition, IRBs will approve all advertising materials 
used for subject recruitment and any educational materials given to the subject. Annual 
reports and progress reports will be submitted to the IRB annually or at a frequency 
requested by the IRB.
The IRB must be a properly constituted board or committee operating in accordance with 
GCP Title 21 Part 56 of the US CFR relating to IRBs and the ICH Guideline for GCP (E6).
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16.4 Informed Consent/HIPAA Authorization
Properly executed written informed consent, in compliance with 21 CFR 50 and ICH 
guidelines, shall be obtained from each subject before entering the subject into the trial.  
Attention is directed to the basic elements that are required in the informed consent under 
US Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a]).  Additional 
elements of informed consent, if appropriate, must be included in the informed consent 
document (21 CFR 50.25[b]). A standard Informed Consent document will be approved by a 
central IRB
  Any study site that requires a site-specific Informed Consent document 
must have the document IRB-approved and the final IRB-approved document must be 
provided to the Sponsor for regulatory purposes.
All potential subjects for the study will be given a current copy of the Informed Consent 
Form to read.  The Site Investigator, sub-investigators, or study physician at each site will 
explain all aspects of the study in lay language and answer all of the subject’s questions 
regarding the study. If the subject desires to participate in the study, s/he will be asked to 
sign the Informed Consent.  Evidence of subject’s understanding will be demonstrated by 
written examination that the subject must pass at 100%.  No subject will undergo any study 
procedures before signing the Informed Consent form, which should be signed before 
screening.  A signed copy will be given to the subject and a signed copy shall be maintained 
in the subject’s clinical file as well as the Regulatory Binder at each study site.  Subjects who 
refuse to participate or who withdraw from the study will be treated without prejudice.
Each subject must also sign a HIPAA (US Health Insurance Portability and Accountability 
Act) form before his/her participation in the study.  A signed copy must be provided to the 
subject and a signed copy shall be maintained in the subject’s clinical file.
16.5 Drug Accountability
All study drug required for completion of this study will be provided by the Sponsor 
(USWM).  Upon receipt, the investigator/pharmacist is responsible for taking inventory of
the investigational agents.  A record of this inventory must be kept and usage must be 
documented.  Any unused or expired investigational agent shall be returned to the Sponsor.
16.6 Outside Monitoring
16.6.1 
Data and Safety Monitoring Board (DSMB)
Adverse event data reported during the study will be reviewed by a Data and Safety 
Monitoring Board (DSMB) comprised of outside experts in substance abuse treatment, 
clinical trials, and biostatistics.  The DSMB will meet by conference call or WebEx every 
3 months during the life of the study to review adverse event and serious adverse data tables 
and data listings.  Any serious adverse event requiring expedited reporting to the FDA will be 
reviewed immediately by the DSMB.  The board will be blinded to subjects’ actual treatment 
assignments, but may break the blind if safety concerns arise from the blinded data.  
Although the DSMB may also have access to efficacy data, it will not be commissioned to 
recommend trial termination due to superior treatment efficacy versus placebo, and the trial 
will not be stopped prematurely for that reason.
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16.6.2 
Medical Monitor
The Sponsor’s (USWM) Medical Monitor will be responsible for attempting to establish 
concurrence with the Site Investigator on the severity and seriousness of any AEs and SAEs, 
the relatedness to the study treatments, the expectedness of the event, and for determining if 
the SAE should be reported to the FDA in a 7- or 15-day expedited report or an annual report 
(Appendix 6).  The Sponsor’s Medical Monitor will also be responsible for tracking and 
assessing trends in the SAEs reported. Further, the Medical Monitor is available to consult 
with the Site Investigators and coordinators on any medical issues related to the study 
(e.g., admission criteria, concomitant medications).
16.6.3 
Clinical Monitors
All Investigators will allow the Sponsor or its representatives to periodically audit, at 
mutually convenient times during and after the study, all eCRFs and corresponding source 
documents for each subject. These monitoring visits will provide an opportunity for 
evaluation of the progress of the study and to inform the Sponsor of potential problems.
The study will be monitored according to an approved monitoring plan.  The monitors will 
assure that submitted data are accurate and in agreement with source documentation; verify 
that investigational agents are properly stored and accounted for; verify that subjects’ consent 
for study participation has been properly obtained and documented; confirm that research 
subjects entered into the study meet inclusion and exclusion criteria; and assure that all 
essential documentation required by GCP guidelines are appropriately filed.
Monitors will conduct a site initiation visit before the start of the study for any 
investigational site not represented at the investigator meeting.  At this visit, the monitor will 
assure that proper study-related documentation exists, assist in training investigators and 
other site personnel in study procedures and GCP guidelines, confirm receipt of study 
supplies, and assure that acceptable facilities are available to conduct the study.
Routine monitoring visits by USWM or designee will be scheduled at appropriate intervals 
but more frequently at the beginning of the study. At these visits, the monitors will verify 
that study procedures are being conducted according to the protocol guidelines and review 
AEs and SAEs. At the end of the study, they will advise on storage of study records and 
return of unused study agents. All sites should anticipate visits by the Sponsor, its
representatives, and the FDA.
16.7 Adverse Event Reporting
In accordance with FDA reporting requirements, all AEs occurring during the course of the 
clinical trial will be collected, documented, and reported by the Site Investigator or sub-
investigators according to the specific instructions detailed in this section of the protocol and 
Appendix 6.  The occurrence of AEs will be assessed starting at the treatment phase of the 
protocol.
An AE is defined as any reaction, side effect, or untoward event that occurs during the course 
of the clinical trial, whether or not the event is considered related to the investigational agent 
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or clinically significant.  For this study, events reported by the subject, as well as clinically 
significant abnormal findings on physical examination or laboratory evaluation will be 
recorded in the subject’s source document and on the AE eCRF.  A new illness, symptom, 
sign or clinically significant clinical laboratory abnormality or worsening of a pre-existing 
condition or abnormality is considered an AE.  Stable chronic conditions, such as arthritis, 
which are present before clinical trial entry and do not worsen are not considered AEs.
After each AE assessment, the physician will record in the subject’s source document and on 
the AE eCRF the type of AE and whether serious (SAE) or non-serious, severity of each AE, 
and the relationship to the study agent. These categories are asking for the physician’s best 
judgment of the severity and relatedness of each AE.  The physician will also record, based 
on his/her best judgment, whether the AE is secondary to opioid withdrawal (see 
Section 15.4.8).  In general, an AE should not be marked as withdrawal related AND related 
to study medication.
Each day, a study physician must review any AEs that are reported as beginning or as 
continuing.  All AEs, including clinically significant abnormal findings on laboratory 
evaluations, regardless of severity, will be followed by a study physician until satisfactory 
resolution.
16.8 Serious Adverse Events (SAEs)
Each adverse event or reaction will be classified by the Site Investigator as serious or 
non-serious. Based on the seriousness of the adverse event or reaction, appropriate reporting 
procedures will be followed.
The Code of Federal Regulations (CFR) Title 21 part 312.32 and ICH Guideline for Industry: 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
ICH-E2A March 1995, as implemented by the US FDA, defines a SAE or serious adverse 
drug experience as any untoward medical occurrence at any dose that:
x
results in death during the period of protocol-defined surveillance;
x
is life-threatening;
x
requires inpatient hospitalization or prolongation of existing hospitalization;
x
results in persistent or significant disability or incapacity; or
x
results in a congenital anomaly/birth defect.
Important medical events that may not result in death, be life–threatening, or require 
hospitalization may be considered SAEs when, based on appropriate medical judgment, the
event may jeopardize the subject and might require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.
An unexpected event is one that is not described with respect to nature, severity, or frequency 
in the product package insert or Investigator’s Brochure.
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All subjects with SAEs must be followed up for outcome. If a study subject withdraws from 
the study or if an investigator decides to discontinue the subject from the study because of a 
SAE, the subject must have appropriate follow-up medical monitoring including, if 
necessary, hospitalization.
Reporting requirements for SAEs are described in detail in Appendix 6. There can be serious 
consequences including ultimately, criminal and/or civil penalties for sponsors who fail to 
comply with FDA regulations governing the reporting of SAEs to the FDA. Any SAEs, 
including death due to any cause, which occurs to any subject entered into treatment in this 
study or within 30 days following cessation of the last dose of treatment with the study 
medication, whether or not considered related to the investigational product, must be reported 
within 24 hours, from the time any study staff member is made aware of such, to the Sponsor 
(USWM).
16.8.1 
Clarification of Serious Adverse Events
x
Death is an outcome of an AE, and not an AE in itself.  In reports of death due to 
“Disease Progression,” where no other information is provided, the death will be 
assumed to have resulted from progression of the disease being treated with the study 
treatment(s).
x
All deaths, regardless of cause or relationship, must be reported for subjects on study 
and for deaths occurring within 30 days of last study treatment or within 30 days of 
last study evaluation, whichever is longer.
x
“Occurring at any dose” does not imply that the subject is receiving study treatment at 
the time of the event.  Dosing may have been given as treatment cycles or interrupted 
temporarily before the onset of the SAE; however, administration of study drug may 
have contributed to the event.
x
“Life-threatening” means that the subject was at immediate risk of death from the 
event as it occurred.  This does not include an event that might have led to death if it 
had occurred with greater severity.
x
Complications that occur during hospitalizations are AEs.  If a complication prolongs 
the hospitalization, it is a SAE.
x
“In-patient hospitalization” means the subject has been formally admitted to a 
hospital for medical reasons, for any length of time.  This may or may not be 
overnight.  It does not include presentation and care within an emergency department.
x
The Investigator should attempt to establish a diagnosis of the event on the basis of 
signs, symptoms, and/or other clinical information.  In such cases, the diagnosis 
should be documented as the AE and/or SAE and not the individual signs/symptoms.
A distinction should be drawn between seriousness and severity of AEs.  An AE that is 
assessed as severe should not be confused with a SAE.  Severity is a category used for rating 
the intensity of an event, and both AEs and SAEs can be assessed as severe (see Appendix 6
for assessment of the intensity of an AE).  An event is defined as "serious" when it meets one 
of the predefined outcomes described above.
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16.9 Overdose
Any accidental or intentional overdose (any increase in frequency or dosage of study 
treatment [lofexidine] that exceeds total dosing of 3.2 mg per day), misuse or abuse of study 
treatment, whether suspected or confirmed, and whether or not associated with an adverse 
experience, must be reported within 24 hours to USWM or designee. This will include 
providing details of signs or symptoms, clinical management, and outcome if available.
Any clinical sequelae in association with the overdose should be reported as an AE as 
outlined in Section 16.7 or SAE as outlined in Section 16.8.  An overdose will be considered 
a SAE only if any of the seriousness criteria are met in Section 16.8.
16.10 Pregnancy
Although pregnancy is not considered an AE, it is the responsibility of the Site Investigator 
or his or her designee to report any pregnancy in a subject (spontaneously reported to them or 
discovered during a protocol-defined pregnancy test) that occurs during the study or within 
30 days of completing the study medication.  All subjects who become pregnant must be 
withdrawn from study medication and must be followed to the completion/termination of the 
pregnancy.  If the pregnancy continues to term, the outcome (health of infant) must also be 
reported to the Sponsor.
17 STATISTICAL APPROACH
17.1 General Considerations
Continuous or ordered categorical variables not subject to censoring will be summarized with 
the mean, standard deviation, minimum, 25th percentile, median, 75th percentile, and 
maximum. Continuous or ordered categorical variables subject to censoring (e.g., time to 
removal from study treatment) will be summarized by the 25th percentile, median, 75th 
percentile derived from Kaplan-Meier estimates of probabilities. Unordered categorical 
variables will be summarized with counts and percentages. Descriptive statistics will be 
provided for each treatment group separately as well as all subjects combined. Additionally, 
descriptive statistics will be provided by gender.
Detailed methodology for the summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be prepared as a 
standalone document and finalized before database lock and unblinding of treatment 
assignments.
17.2 Days 1-7 (Randomized, Double-Blind, Placebo-Controlled Treatment)
It is hypothesized that a daily dose of either 2.4 mg or 3.2 mg lofexidine will achieve greater 
efficacy than placebo with respect to overall symptom relief over the first 7 days of opioid 
withdrawal (primary endpoint) and will increase the likelihood of subjects completing 
Days 1-7 of treatment (secondary endpoint). Further, safety measures in the 2.4 mg and 
3.2 mg total daily dose groups will be compared descriptively to assess whether the lower 
dose results in fewer and less severe adverse events than does the higher dose.
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17.2.1 
Analysis Populations
Three principal analysis populations are defined as follows:
x
Intent-to-treat (ITT), consisting of all randomized subjects.  Subjects will be assigned 
for analysis according to the group to which they are randomized.
x
Modified intent-to-treat (mITT), consisting of all subjects in the ITT group who 
received at least one dose of study medication.
x
Safety consisting of all subjects who received at least one dose of study medication.
The principal analysis population for the analyses of demographics and baseline 
characteristics and efficacy will be the mITT population. Sensitivity analyses of the
completion status endpoint will be carried out on the ITT population. Safety summaries will 
be provided for the Safety population. Data recorded on subjects who are in the ITT but not 
in the mITT or Safety populations will be included in data listings.
17.2.2 
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized descriptively.
17.2.3 
Subject Disposition
Subject disposition will be summarized descriptively.
17.2.4 
Primary Efficacy Endpoint 
The primary efficacy endpoint is:
x
AUC based on SOWS-Gossop scores from Days 1 through 7.
17.2.5 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is:
x
Completion status (i.e., whether a subject receives at least one dose of study 
medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7).
17.2.6 
Tertiary/Exploratory Endpoints 
The tertiary/exploratory endpoints are:
x
SOWS-Gossop, OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and 
COWS scores on Days 1, 2, 3, 4, 5, 6, and 7;
x
Retention analysis (time to removal from study treatment) over the 7 inpatient days;
x
Concomitant medication analysis;
x
Withdrawal-related AE analysis; 
x
Evaluation of subject treatment status 30 days post discharge;
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x
Status of detoxification on Day 7 or early termination as assessed by the 
Site Investigator; and
x
In addition, single items (e.g., sweating, anxiety) from the OOWS-Handelsman and 
COWS that are not included in the SOWS-Gossop may be analyzed, as may AUC
based on COWS scores from Days 1 through 7.
17.2.7 
Control of the False Positive Rate and Statistical Testing Strategy
All statistical tests for efficacy will be one-sided. For the primary and secondary endpoints,
the treatment comparisons subject to control of the false positive rate will be 3.2 mg 
lofexidine vs. placebo and 2.4 mg lofexidine vs. placebo. (Comparisons of 3.2 mg vs. 2.4 mg 
will be descriptive.) The familywise error rate (FWE) for the collection of primary and 
secondary endpoint comparisons will be controlled at the 0.025 level, one-sided, by a 
sequential testing strategy in which hypotheses are tested in the following order, each at the 
0.025 level, one-sided.
1. Primary: AUC(1-7), 3.2 mg lofexidine versus placebo;
2. Primary: AUC(1-7), 2.4 mg lofexidine versus placebo;
3. Secondary: Completion rate, 3.2 mg lofexidine versus placebo; and
4. Secondary: Completion rate, 2.4 mg lofexidine versus placebo.
Adjusted p-values for these 4 treatment comparisons, based on this sequence of statistical 
tests, are defined in the table below.
Test 
Order
Endpoint Comparison
P-value
Unadjusted (a)
Adjusted
1
AUC(1-7), 3.2 mg vs placebo
p1
p1
2
AUC(1-7), 2.4 mg vs placebo
p2
max(p1, p2)
3
Completion rate, 3.2 mg vs placebo
p3
max(p1, p2, p3)
4
Completion rate, 2.4 mg vs placebo
p4
max(p1, p2, p3, p4)
(a) P-values p1 and p2 are one-sided, derived from the statistical test described in Section 17.2.8.1;
p-values p3 and p4 are one-sided, derived from the statistical test described in Section 17.2.8.2. 
Any adjusted p-value less than 0.025 in magnitude will be declared statistically significant.
The tertiary/exploratory endpoints will be tested without multiplicity adjustment.
17.2.8 
Statistical Methods for Efficacy
17.2.8.1 
SOWS-Gossop AUC(1-7)
A pattern-mixture approach [21], with subjects stratified by disposition within Days 1-7, 
will be used in assessing SOWS-Gossop AUC(1-7). The 4 disposition strata are subjects: 
who complete Days 1-7 of the study (see Section 17.2.5); who discontinue due to lack of 
efficacy (including adverse events related to opioid withdrawal); who discontinue due to 
adverse 
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events related to intolerability or toxicity to study drug; and who discontinue for other 
reasons. The inference is comprised of several steps:
1. Transformation. Because of the inherent skewness in the SOWS-Gossop scores the raw
data will first be transformed to the logarithm of the score plus 1.0.
2. Modeling. A linear mixed effects repeated-measures model will be constructed for the
SOWS-Gossop score. The fixed effects will be disposition stratum, treatment and time,
and their interactions, as well as a main effect of gender (randomization stratification
factor) and baseline SOWS-Gossop score as a one degree of freedom covariate.  For each
combination of treatment and stratum, the time course will be modeled as a linear change
point model, allowing for one slope between Days 1 and 2 and a possibly different slope
from Days 2 through 7. The model will parameterized to ensure that the predictions from
the two line segments agree at Day 2. Subjects will be treated as a random effect, and the
slope and intercept parameters will be treated as random coefficients.  Modeling the time
course, rather than using each time point as a discrete level of a model factor, allows
estimation of group means through Day 7 even in the non-completer strata. The choice
of Day 2 as the change point is based on prior lofexidine studies, in which SOWS-Gossop
mean scores in the placebo group increased from Day 1 to Day 2 and then decreased
through Day 7. The modeling allows a different time course for each of the lofexidine
dose groups.
3. Point estimates of AUC(1-7). For each combination of disposition stratum, treatment
and study day, the estimated least squares means SOWS-Gossop (on the log scale) for
males and females will be combined using a weighted average, the weights being the
relative proportions of males and females in the mITT population. The results will then
be transformed back to the original SOWS-Gossop scale of measurement, from which
point estimates of AUC(1-7) for each combination of stratum and treatment will be
computed using the trapezoidal rule. It should be noted that these calculations will not be
derived from AUC(1-7) computed within individual subjects, many of whom will have
incomplete data for the later study days in Days 1-7. In particular, there will be no
imputation of data for individual subjects.
4. Estimates of treatment effect. For each active treatment, the treatment effect (lofexidine
3.2 mg versus placebo or lofexidine 2.4 mg versus placebo) will be estimated with
respect to AUC(1-7) within each disposition stratum. Then a weighted average of
treatment effects will be computed, where the weights are the relative proportions of
subjects in the 4 strata.
5. Interval estimates of AUC(1-7) and hypothesis testing. The covariance matrix of the
mixed model’s estimated fixed effects will be used with standard linear model methods to
derive the covariance matrix of the weighted average of male and female log-transformed
SOWS-Gossop scores. The multivariate delta method will be used to derive the
covariance matrix of the back-transformed SOWS-Gossop time course. Standard linear
model methods will then be used to derive the covariance matrix of the weighted average
of AUC(1-7) treatment effects, from which confidence intervals and p-values will be
derived.
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17.2.8.2 
Completion Status
The proportion of subjects in each treatment arm who receive at least one dose of study 
medication on Day 7 and complete the 3.5-hour post-dose SOWS-Gossop assessment on 
Day 7 will be analyzed using Cochran-Mantel-Haenszel tests, with gender as the stratifying 
factor. One test will compare the 3.2 mg lofexidine group to placebo; a second will compare 
the 2.4 mg lofexidine group to placebo.
17.2.8.3 
SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7
The pattern-mixture approach, with the same stratification and treatment of gender used for 
the AUC(1-7) analysis, will be used to assess treatment effect with respect to SOWS-Gossop 
on Days 1, 2, 3, 4, 5 and 6 (but not 7). A single linear mixed effects repeated-measures 
model will be constructed for the transformed SOWS-Gossop score. Subject will be a 
random effect. The fixed effects will be disposition stratum, treatment and time, with each 
study day as a discrete level of the time factor, and their interactions. Estimated means for 
each combination of stratum, treatment and day will be back-transformed to the original 
SOWS-Gossop scale of measurement. Like the AUC(1-7) calculation, the weighted average 
of treatment effects will be calculated along with confidence intervals and p-values. This 
approach will provide no information on the non-completer strata on Day 7. Therefore, the 
modeled time course from the AUC(1-7) analysis will be used to estimate SOWS-Gossop on 
Day 7 for all combinations of disposition stratum and treatment, and Day 7 comparisons will 
be based on these estimates.
17.2.8.4 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS
The same methods used for SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7 will be used for 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS scores on Days 1, 2, 3, 
4, 5, 6, and 7. Types of data transformation, if any, to be used before mixed effects 
modeling, will be specified in the SAP.
17.2.8.5 
Retention Analysis (Time to Removal from Study Treatment)
Time to removal from study treatment is defined as the last study day on which the subject 
received treatment. The time for subjects who complete some but not all treatment on Day 7
will be Day 7, uncensored. Subjects who complete all treatments on Day 7 will be censored 
at Day 7. This endpoint will be summarized descriptively for each combination of treatment 
group and gender with Kaplan-Meier curves and tabulations of the number and percentage of 
subjects newly removed from receiving study treatment on each of inpatient Days 1 to 7.
Each lofexidine dose group will be compared inferentially to placebo with a Cox 
proportional hazards regression model of time to removal from study, stratified by gender, 
with treatment as the independent variable. The estimated hazards ratio will be reported as a 
descriptive measure. The p-value on the log hazards ratio will be converted to a one-tailed 
p-value by considering whether the hazard ratio indicates a delay in time to removal in the 
lofexidine group versus the placebo group.
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17.2.8.6 
Concomitant Medication Analysis
For each of Days 1 to 7, each subject’s number of concomitant medication doses taken will 
be treated as a continuous variable. Descriptive statistics will be provided on the as-observed 
data on each study day.  In addition, least squares means and p-values comparing each 
treatment to placebo will be obtained with the same methods used for SOWS-Gossop on 
Days 1, 2, 3, 4, 5, 6, and 7. Types of data transformation, if any, to be used before mixed 
effects modeling, will be specified in the SAP.
17.2.8.7 
Status of Detoxification on Day 7 or Early Termination as Assessed by the 
Site Investigator
Descriptive statistics (numbers and percentages) on the status of detoxification 
(successful/unsuccessful) as assessed by the Site Investigator at Day 7 or early termination 
will be presented by treatment group overall and by gender within treatment group.
17.2.8.8 
Single Items from the OOWS-Handelsman and COWS, and COWS AUC(1-7)
Single items (e.g., sweating, anxiety) from the OOWS-Handelsman and COWS that are not 
included in the SOWS-Gossop may be analyzed; the scores will be treated as continuous 
variables and analyzed using the same methods used for SOWS-Gossop on Days 1, 2, 3, 4, 5, 
6, and 7. COWS AUC(1-7) may also be analyzed; a modeling approach analogous to the 
modeling of SOWS-Gossop AUC(1-7) will be used. While the functional form of the time 
course for SOWS-Gossop is based on historical data, the functional form of the time course 
for COWS will be based on the data from this study.
17.2.9 
Power Calculations
Treatment effect and subject variability with respect to SOWS-Gossop scores were estimated 
from the prior Phase 3 study (USWM-LX1-3002), using the random coefficients model 
planned for the present study and estimating the treatment effect of 3.2 mg lofexidine versus 
placebo with respect to AUC(1-7). It was assumed that the treatment effect of the 2.4 mg 
lofexidine dose will be three-fourths the treatment effect of the 3.2 mg dose. The table below 
shows the power to find a significant treatment effect for the comparisons of the two 
lofexidine treatments versus placebo, assuming a sample size allocation ratio of 3:3:2 
(3.2 mg lofexidine : 2.4 mg lofexidine : placebo) and accounting for the sequential testing 
approach described in Section 17.2.7. The power to find a statistically significant effect of 
the 3.2 mg lofexidine dose with respect to AUC(1-7) is in excess of 90% with the planned 
total sample size of 600.
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Power (%) with Respect to AUC(1-7)
Total 
Sample Size
3.2 mg Lofexidine 
versus Placebo
2.4 mg Lofexidine 
versus Placebo
600
94.6
72.6
550
92.6
67.6
500
90.1
62.2
450
86.8
55.7
17.2.10 Subgroup Analyses
The models used for the primary analysis will be modified for each of several subgroups to 
include the subgroup and its interaction with treatment as a fixed effect.  Subgroups include 
age, gender, and race. The SAP will list all subgroups to be analyzed, their classifications 
(e.g., age dichotomization, race groupings), and modeling details.
17.2.11 Safety Measures
The safety measures during Days 1-7 of the study are AEs, vital signs, ECGs (primarily 
evaluated for changes in QTcF versus time-matched controls for both doses of lofexidine and 
placebo), clinical laboratory measures, and physical exams. Adverse event summaries will 
include tabulations overall and by seriousness, severity, and causality assessment. The data 
from these measures recorded during Days 1-7 will be summarized descriptively by 
treatment group.  In addition, each lofexidine group will be compared inferentially to the 
placebo group using chi-square tests for categorical variables and t-tests within an analysis of 
variance for continuous variables; the resulting p-values will not be adjusted for multiple 
testing.
17.3 Days 8-14 (Open-Label, Continuation Treatment)
Safety and effectiveness endpoints for Days 8-14 will be summarized by randomized 
treatment group.
17.3.1 
Assessment of Effectiveness
Summary statistics will be provided by treatment day (overall and by gender) for:
x
SOWS-Gossop;
x
OOWS-Handelsman;
x
MCGI (Subject and Rater);
x
VAS-E; and
x
COWS.
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In addition, the following will be summarized overall and by gender over Days 8-14:
x
Duration of exposure;
x
Number and proportion of subjects successfully completing detoxification as assessed 
by the Site Investigator;
x
Distribution of number of days required to complete detoxification as assessed by the 
Site Investigator;
x
Average daily dose of lofexidine; and
x
Concomitant medications.
17.3.2 
Assessment of Safety
Safety measures will be summarized for the following subject cohorts:
x
All treated subjects;
x
Treated subjects without urinary evidence of illicit drug use; and
x
Treated subjects with urinary evidence of illicit drug use (may be further subdivided 
by type of illicit drug used).
Descriptive statistics will be provided for:
x
All AEs;
x
New onset AEs (including those observed during Days 1-7 whose severity during 
Days 8-14 is greater than observed during Days 1-7);
x
Vital signs;
x
ECGs;
x
Clinical laboratory tests; and
x
Physical examinations.
18 DATA MANAGEMENT AND CASE REPORT FORMS (CRFS)
Data management activities and statistical analytical support will be coordinated through the 
CRO
The CRO will be responsible for the construction and 
accuracy of the study database.
18.1 Data Collection
Data will be collected at the study sites on source documents, which will be entered at the 
site into electronic CRFs (eCRFs). The eCRFs will be supplied by the CRO. CRFs are to be 
completed on an ongoing basis during the study. The medical chart and the source 
documents are the source of verification of data. CRFs should be completed according to the 
instructions in the study operations manual.
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The Site Investigator is responsible for maintaining accurate, complete, and up-to-date 
records for each subject. The Site Investigator is also responsible for maintaining any source 
documentation related to the study, including any films, lab reports, or ECG tracings.
Data generated by this study must be available for inspection by representatives of the 
US FDA, the Sponsor (USWM), the Sponsor representatives, the central IRB 
, and 
the site’s IRB.
18.2 Electronic Data Capture
Data entered by site personnel into the electronic data capture (EDC) system will be 
reviewed by the CRO.  If incomplete or inaccurate data are found, a query in the EDC system 
will be generated for response by the clinical site. Sites will promptly resolve data 
inconsistencies and errors.  An audit trail of any corrections or changes to the data in the 
EDC system will be maintained.  USWM will receive reports at least monthly regarding the 
quality and quantity of data submitted to the CRO.
Site Investigators agree to routine data audits by the staff of USWM.  USWM monitors will 
routinely visit each site to assure that data entered in the EDC system are in agreement with 
source documents at the sites.  The monitors will also verify that investigational agents have 
been properly stored and accounted for, subject informed consent for study participation has 
been obtained and documented in the subject’s progress notes, all essential documents 
required by GCP regulations are on file, and sites are conducting the study according to the 
research protocol.
18.3 Data Analysis
When the study is completed, all data have been entered into the clinical database, and the 
final database has been locked, statistical analysis of the data will be performed by the 
CRO’s statisticians or an independent statistician in accordance with the Analytical Plan of 
this protocol (see Section 17) and detailed in the SAP.  Periodically, during the investigation, 
the CRO will also prepare summary reports of the data, with no identification or grouping by 
randomized treatment, so that progress of the study can be monitored.  Various reports will 
be prepared for USWM and others, as appropriate.
18.4 Study Documentation and Records Retention
Study documentation includes all eCRFs, data correction forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence 
and regulatory documents (e.g., signed protocol and amendments, IRB correspondence and 
approved consent form and signed informed consent forms, Statement of Investigator form, 
and clinical supplies receipt and distribution records).
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. Accordingly, source documents include, but are not limited to, laboratory reports, 
ECG tracings, x-rays, radiologist reports, subject diaries, biopsy reports, ultrasound 
photographs, subject progress notes, hospital charts or pharmacy records, and any other 
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similar reports or records of any procedure performed in accordance with the protocol.  
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.  Any duplicate of a source document to be retained as a 
part of a eCRF should maintain subject confidentiality per HIPAA.
Government agency regulations and directives require that the investigator must retain all 
study documentation pertaining to the conduct of a clinical trial. These documents must be 
kept for a minimum of 2 years after the approval of a new drug application (NDA) and 
finalization of all marketing strategies, or if the NDA is not approved, for 2 years after 
discontinuation of the IND, whichever is the later. In all instances sites must get permission 
from USWM before disposition of any study documentation and materials.
18.5 Confidentiality
18.5.1 
Confidentiality of Data
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom 
of Information Act providing, in part, that proprietary information furnished to clinical 
investigators and IRBs will be kept confidential by the FDA only if maintained in confidence 
by the Site Investigator and IRB.
By participating in this protocol the Site Investigator affirms to USWM that information 
furnished to the Site Investigator by USWM will be maintained in confidence and such 
information will be divulged to the IRB, Ethical Review Committee (or similar or expert 
committee), affiliated institution, and employees only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution, and employees.
18.5.2 
Confidentiality of Subject Records
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports, and other 
records will be coded using alpha-numeric identifiers only.  Only research and clinical 
records will be stored in a locked cabinet.  Only research staff and USWM officials will have 
access to the records.  Subject information will not be released without written permission, 
except as necessary for monitoring by the FDA or USWM.  USWM will file for a Certificate 
of Confidentiality that will cover all sites participating in the study (see Appendix 7).
By participating in this protocol the investigator agrees that within local regulatory 
restrictions and ethical considerations, USWM or any regulatory agency may consult and/or 
copy study documents in order to verify eCRF data.
Subject confidentiality will be maintained in any publications or presentations that result 
from this study.
19 PUBLICATIONS OF THE STUDY RESULTS
It is understood by the Site Investigator that the information generated in this study will be 
used by the Sponsor (USWM) in connection with the development of the product and 
therefore may be disclosed to government agencies in various countries.  To allow for the use 
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of information derived from the study, it is understood that the Site Investigator is obliged to 
provide the Sponsor with complete test results, all study data, and access to all study records.
The Sponsor recognizes the importance of communicating medical study data and therefore 
encourages their publication in reputable scientific journals and at seminars or conferences.  
Because this is a multicenter study, the combined results of the study will be published 
before the Investigator submits site-specific results for publication.  Any results of medical 
investigations with the Sponsor’s products and/or publication/lecture/manuscripts based 
thereon, shall be exchanged and discussed by the Site Investigator and Sponsor 
representative(s) 60 days before submission for publication or presentation.  Due regard shall 
be given to the Sponsor’s legitimate interests, e.g., manuscript authorship, obtaining optimal 
patent protection, coordinating and maintaining the proprietary nature of submissions to 
health authorities, coordinating with other ongoing studies in the same field, and protecting 
confidential data and information.
The Sponsor shall be furnished with a copy of any proposed publication.  In cases of 
publications or presentations of material arising from multicenter clinical investigations, the 
Sponsor is to serve as coordinator and referee.  Individual investigators who are part of a 
multicenter investigation may not publish or present data that are considered common to a 
multicenter investigation without the consent of the other participating investigators and the 
prior review of the Sponsor.  In case of disagreement amongst the investigators participating 
in a multicenter investigation, the Sponsor will be the final arbiter.  Sponsor comments shall 
be given without undue delay, and not later than within 60 days.  If they are not accepted, the 
senior author of the manuscript and the Sponsor’s representatives shall promptly meet to 
discuss further and endeavor to agree on the final wording and/or disposition of the 
publication.  The above procedure also applies to studies that are not completed, including 
those that are prematurely discontinued.
Results from investigations shall not be made available to any third party by the investigating 
team outside the publication procedure as outlined previously.  The Sponsor will not quote 
from publications by investigators in its scientific information and/or promotional material 
without full acknowledgment of the source (i.e., author and reference).
20 PROTOCOL ADHERENCE AND AMENDMENTS
The Site Investigator and each sub-investigator must adhere to the protocol as detailed in this 
document. Only the Sponsor (USWM) may modify the protocol.  All amendments that have 
an impact on subject risk or the study objectives, or require revision of the informed consent 
document, must receive approval from the DSMB and central IRB/individual site’s IRB 
before their implementation.
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21 QUALITY CONTROL AND QUALITY ASSURANCE
Following written standard operating procedures, study monitors will verify that the clinical 
trial is conducted and data are generated, recorded, and reported in compliance with the 
protocol, GCP, and applicable regulatory requirements.  Reports on monitoring activities will 
be submitted to the Sponsor.
The Sponsor (USWM) will secure agreement from all involved parties to ensure direct access 
to all trial-related sites, source data/documents, and reports for the purpose of monitoring and 
auditing by the Sponsor, and inspection by local and regulatory authorities.
The CRO 
will be the Data Coordinating Center and will 
implement quality control procedures in accordance with GCPs and their internal Standard 
Operating Procedures, beginning with the data entry system and generate data quality control 
checks that will be run on the database.  Any missing data or data anomalies will be 
communicated to the site for clarification and resolution.
22 REFERENCES
1.
Substance Abuse and Mental Health Services Administration (SAMHSA), Office of
Applied Studies (2008).  Results from the 2007 National Survey on Drug Use and
Health:  National Findings (NSDUH Series H-34, DHHS Publication No. SMA
08-4343).  Rockville, MD.  http://oas.samhsa.gov
2.
National Institutes of Health.  Fact Sheet-Heroin Addiction.  September 2006.
Bethesda, MD.
http://www.nih.gov/about/researchresultsforthepublic/HeroinAddiction.pdf
3.
Archibold RC.  In heartland death, traces of heroin’s spread.  New York Times.
May 30, 2009. http://www.nytimes.com/2009/05/31/us/31border.html
4.
The DAWN Report.  Trends in emergency department visits involving nonmedical use
of narcotic pain relievers.  June 18, 2010.
http://oas.samhsa.gov/2k10/dawn016/opioided.htm
5.
Methadone is a schedule II drug.  See 21 C.F.R. § 1308.12(c)(10) (isomethadone);
§ 1308.12(c)(15) (methadone); and § 1308.12(c)(16) (methadone-intermediate,
4-cyano-2-dimethylamino-4,4-diphenyl butane).  Buprenorphine is a schedule III drug.
See 21 C.F.R. § 1308.13(e)(2)(i).
6.
Gowing L, Farrell M, Ali R, White JM.  Alpha 2-adrenergic agonists for the
management of opioid withdrawal.  Cochrane Database Syst Rev 2008, Issue 4.
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Kahn A, Mumford JP, Rogers GA, Beckford H.  Double-blind study of lofexidine and
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Lin SK, Strang J, Su LW, Tsai CJ, Hu WH.  Double-blind randomized controlled trial
of lofexidine versus clonidine in the treatment of heroin withdrawal.  Drug Alcohol
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Carnwath T, Hardman J.  Randomised double-blind comparison of lofexidine and
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Gerra G, Zaimovica A, Giusti F, et al.  Lofexidine versus clonidine in rapid opiate
detoxification.  J Subst Abuse Treatment 2001;21:11-17.
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Yu E, Herman BH, Miotto K, et al.  In-patient safety evaluation of lofexidine (alpha-2
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Yu E, Miotto K, Akerele E, et al.  A phase 3 placebo-controlled, double blind, multi-
site trial of the α2-noradrenergic agonist, lofexidine, for opioid withdrawal.  Drug
Alcohol Depend 2008;97:158-168.
13.
Gorodetzky CW.  A phase III, randomized, multi-center, double blind, placebo
controlled study of safety and efficacy of lofexidine for relief of symptoms in subjects
undergoing inpatient opiate detoxification.  US WorldMeds Report for Protocol
USWM-LX1-3002, March 14, 2010.
14.
Heyman ER.  An open-label, single-dose, pilot study to determine the maximum
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and
women.  CardioCore Report 01496KM, April 27, 2010.
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Leibowitz MT.  An open-label, single-dose, pilot study to determine the maximum
tolerated dose, pharmacokinetics, and QTc effects of lofexidine in healthy men and
women.  CEDRA Report DCN 01496KM, April 22, 2010.
16.
Gossop M.  The development of a short opiate withdrawal scale (SOWS).  Addict
Behav 1990;15(5):487-490.
17.
Medical Outcomes Systems.  M.I.N.I. International Neuropsychiatric Interview
(M.I.N.I.), version 6.0 (10/10/10).  https://www.medical-outcomes.com/index/mini/.
08 March 2013.
18.
Sheehan DV, Lecrubier Y, Harnett-Sheehan K, et al. The M.I.N.I. International
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured
diagnostic psychiatric interview. J Clin Psychiatry 1998;59(suppl 20):22-33.
19.
Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD.  Two
new rating scales for opiate withdrawal.  Am J Drug Alcohol Abuse
1987;13(3):293-308.
20.
Wesson DR, Ling W.  The clinical opiate withdrawal scale (COWS).  J Psychoactive
Drugs 2003;35(2):253-259.
21.
Little RJA.  Pattern-mixture models for multivariate incomplete data.  Journal of the
American Statistical Association 1993;88:125-134.
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SAP_000.pdf: 
PRODUCT: LUCEMYRA (Lofexidine) 
STATISTICAL ANALYSIS PLAN PROTOCOL NUMBER: USWM-LX1-3003-1 / 02 
 
  
SPONSOR: 
USWM, LLC (dba US WorldMeds) 
4441 Springdale Rd 
Louisville, KY  40241 
 
 
TITLE: 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety, and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine 
Treatment (Days 8-14) 
 
 
DOCUMENT DATE: 22JAN2015 
NDA NUMBER: 209229 
NCT NUMBER: NCT01863186 


 
US WorldMeds, LLC 
209229 
Clinical Study Report – USWM-LX1-3003-1 
 
 
16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 
Table 1: 
Statistical Analysis Plans 
 
Statistical Analysis Plans Included in Appendix 16.1.9 
16.1.9.1 Statistical Analysis Plan: Clinical Study Report- Version 1.0- 18 June 2014 
16.1.9.2 Statistical Analysis Plan: Clinical Study Report- Addendum 1- 24 December 2014 
16.1.9.3 Statistical Analysis Plan: Clinical Study Report- Addendum 2- 22 January 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Number: USWM-LX1-3003-1 
Statistical Analysis Plan 
Final Version: 1.0 
Issue Date:18-JUN-14 
 
 
 
 
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Effective: 14-Feb-13 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
USWM-LX1-3003-1 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine 
Treatment (Days 8-14) 
Protocol Ref: USWM-LX1-3003-1 
Final Version: 1.0 
Date effective:  18-JUN-14 
 
 
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PROPRIETARY AND CONFIDENTIAL 
SUMMARY OF SECTIONS 
 
1. 
INTRODUCTION ................................................................................................................. 4 
2. 
SAMPLE SIZE ..................................................................................................................... 4 
3. 
RANDOMIZATION .............................................................................................................. 5 
4. 
INTERIM ANALYSIS .......................................................................................................... 5 
5. 
Statistical methods ................................................................................................................. 5 
5.1 
Continuous .................................................................................................................... 5 
5.2 
Categorical .................................................................................................................... 5 
6. 
Analysis Plan ........................................................................................................................ 5 
6.1 
General .......................................................................................................................... 5 
6.2 
Derived Data .................................................................................................................. 6 
6.3 
Analysis populations ....................................................................................................... 7 
6.4 
Protocol Deviations ........................................................................................................ 7 
6.5 
Data Summaries ............................................................................................................. 7 
6.6 
Disposition of Subjects ................................................................................................... 8 
6.7 
Baseline Comparability ................................................................................................... 9 
6.7.1 
Study Population ..................................................................................................... 9 
6.7.2 
Variables Considered ............................................................................................. 10 
6.8 
Measurement of Treatment Compliance .......................................................................... 12 
6.9 
Primary Endpoint ......................................................................................................... 12 
6.9.1 
Principal Analysis ................................................................................................. 13 
6.9.2 
Sensitivity Analysis ............................................................................................... 14 
6.9.3 
Exploratory Analysis ............................................................................................. 15 
6.10 
Secondary Endpoint ...................................................................................................... 16 
6.11 
Tertiary/Exploratory Endpoints ...................................................................................... 16 
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PROPRIETARY AND CONFIDENTIAL 
6.12 
Multiplicity .................................................................................................................. 18 
6.13 
Safety analysis ............................................................................................................. 18 
6.14 
Change to Planned Protocol Analysis ............................................................................. 23 
7. 
References .......................................................................................................................... 24 
8. 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT .................................... 25 
9. 
FIGURES TO BE INCLUDED IN THE CLINICAL STUDY REPORT ................................... 25 
10. 
APPENDIX 16.2 LISTINGS ............................................................................................ 25 
 
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PROPRIETARY AND CONFIDENTIAL 
1.  INTRODUCTION 
This document details the statistical analysis of the data that will be performed by 
 
 for the US WorldMeds, LLC study USWM-LX1-3003-1.  
 
The proposed analysis is based on the contents of the Final Version of the protocol (dated 10-
Aug-2012) and amendments 1 and 2 (dated 08-Mar-13 and 06-May-13 respectively). 
 
The Clinical Study Report will be written by 
 following the guidelines in the ICH E3 
document. 
 
The primary objective of this study is to investigate the efficacy, safety, and dose-response of 
lofexidine (2.4 mg or 3.2 mg per day) in reducing withdrawal signs and symptoms and 
facilitating completion of detoxification/extending treatment retention in subjects undergoing 
detoxification from short-acting opioids in a double-blind inpatient setting (Days 1-7) followed 
by an open-label inpatient/outpatient setting (Days 8-14). 
 
It is hypothesized that a daily dose of either 2.4 mg or 3.2 mg lofexidine will achieve greater 
efficacy than placebo with respect to overall symptom relief over the first 7 days of opioid 
withdrawal (primary endpoint) and will increase the likelihood of subjects completing Days 1-7 
of treatment (secondary endpoint). Further, safety measures in the 2.4 mg and 3.2 mg total daily 
dose groups will be compared descriptively to assess whether the lower dose results in fewer 
and less severe adverse events than does the higher dose. 
2. SAMPLE SIZE 
Treatment effect and subject variability with respect to SOWS-Gossop scores were estimated 
from the prior Phase 3 study (USWM-LX1-3002), using the random coefficients model planned 
for the present study and estimating the treatment effect of 3.2 mg lofexidine versus placebo 
with respect to area under the curve (AUC) based on the SOWS-Gossop scores from Days 1 
through 7 (AUC(1-7)). It was assumed that the treatment effect of the 2.4 mg lofexidine dose 
will be three-fourths the treatment effect of the 3.2 mg dose. The table below shows the power 
to find a significant treatment effect for the comparisons of the two lofexidine treatments versus 
placebo, assuming a sample size allocation ratio of 3:3:2 (3.2 mg lofexidine : 2.4 mg lofexidine 
: placebo) and accounting for the sequential testing approach described in Section 6.1. The 
power to find a statistically significant effect of the 3.2 mg lofexidine dose with respect to AUC 
(1-7) is in excess of 90% with the planned total sample size of 600. 
 
 
Power (%) with Respect to AUC (1-7) 
Total Sample Size 
3.2 mg Lofexidine versus 
Placebo 
2.4 mg Lofexidine versus 
Placebo 
600 
94.6 
72.6 
550 
92.6 
67.6 
500 
90.1 
62.2 
450 
86.8 
55.7 
 
 
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PROPRIETARY AND CONFIDENTIAL 
3. RANDOMIZATION 
A prospective subject who meets all of the study inclusion criteria and does not meet any of the 
exclusion criteria may be randomized into the study. The final eligibility criterion is a score of 
at least 2 on the OOWS-Handelsman at Baseline. 
A stratified randomization procedure will be used to separately allocate male and female 
subjects in 1 of the 3 treatment groups: 2.4 mg lofexidine, 3.2 mg lofexidine, or placebo. 
Randomization will be implemented centrally, that is, take place across all investigational sites 
using an Interactive Web Response System (IWRS) managed by 
Once eligibility criteria 
are confirmed at the Baseline visit, site personnel will access the IWRS and complete 
randomization procedures. The system will assign a unique kit number for drug dispensation 
according to the randomization scheme. The subject number assigned at screening should be 
used throughout the study in all source documents and eCRFs.  
4. INTERIM ANALYSIS 
No interim analysis is planned. 
5. STATISTICAL METHODS 
5.1 Continuous 
Continuous variables and ordered categorical variables not subject to censoring will be 
summarized with the number of non-missing observations, mean, standard deviation, minimum, 
25th percentile, median, 75th percentile, and maximum. Continuous variables subject to 
censoring (e.g., time to removal from study treatment) will be summarized by the number of 
subjects with data, 25th percentile, median, 75th percentile derived from Kaplan-Meier 
estimates of probabilities. 
 
For summary statistics, means, medians and percentiles will be displayed to one more decimal 
place than the raw data, dispersion statistics (e.g. standard deviation) will have two more 
decimal places, and the minimum and maximum will be displayed to the same number of 
decimal places as reported in the raw data. 
 
5.2 Categorical  
Unordered categorical and ordered categorical (depending on the number of categories) 
variables will be presented in contingency tables with cell frequencies and percentages for the 
number of non-missing observations and frequencies for the number of missing observations 
apart from disposition of subjects, concomitant medications, measurement of treatment 
compliance and adverse events where percentages will be presented for the population. 
6. ANALYSIS PLAN 
6.1 General 
The treatment groups will be labelled as 2.4 mg Lofexidine, 3.2 mg Lofexidine and Placebo 
within the statistical output. In addition the 2.4 mg Lofexidine and 3.2 mg Lofexidine doses are 
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combined to form a single Lofexidine treatment group for presentation of safety data.  Subject 
data in Appendix 16.2 listings will be ordered by treatment group, site and subject. 
All statistical tests for efficacy will be 2-sided at the α=0.05 significance level.  
All comparisons between the treatments will be reported with 95% confidence intervals for the 
difference. P-values will be rounded to four decimal places. 
 
Only scheduled post-baseline laboratory and vital signs values will be tabulated.  Post-baseline 
repeat/unscheduled assessments will be disregarded, although they will be listed in the relevant 
appendices to the report; in particular all clinically significant values will be noted. 
 
All calculations and figures will be produced using SAS Version 9.33
 or higher. 
All summaries and analyses documented below will be presented in the final integrated 
statistical/clinical report and tables that will be based on the E3 guidelines published by ICH.  
However, it is noted here that no analysis plan prepared in advance of the data can be 
absolutely definitive and so the final report may contain additional tables or statistical tests if 
warranted by the data obtained.  The justification for any such additional analyses will be fully 
documented in the final report. 
 
6.2 Derived Data 
 
Definition of baseline 
For all variables, baseline is defined as the last non-missing value prior to the receiving the first 
dose of study medication.  
All tabulations involving change from baseline data will only include subjects with cohort data 
i.e. with data at baseline and at follow-up. Change from baseline will be calculated as follow-up 
values minus baseline value. 
 
 
Incomplete dates 
All incomplete dates will be included in the clinical database as they were entered in the eCRF.  
Thereafter for calculation purposes, the incomplete dates will be completed using pre-defined 
rules.  If a day or month is not recorded it will be replaced by the first day of the month or 
January respectively, provided this does not contradict any other dates recorded.  For missing 
adverse events and medications dates/times during the trial, the worst-case date will be used 
(e.g. the end of the month for a stop date and 23:59 for the stop time, the date/time of initial 
dose for start of AE i.e. all events with missing start dates will be assumed to be treatment 
emergent). 
 
 
Ambiguous values 
In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x”, then for analysis purposes 
a value of x will be taken. Where a range of values is quoted the midpoint of the range will be 
taken.  
 
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PROPRIETARY AND CONFIDENTIAL 
 
Questionnaire Data 
In the event that component items used to calculate total scores for questionnaire data e.g. 
SOWS Gossop score are missing then the total scores will also be set to missing. 
 
Site pooling for statistical analyses 
For the purposes of statistical analyses models where site is included within the model as a 
fixed effect, sites randomizing < 6 subjects will be pooled from smallest to largest until the 
pooled site subsequently created has at least 6 subjects. In the event that the pooling of sites 
with less than 6 subjects does not result in a site with > 6 subjects, then that pooled site with < 6 
subjects will also be pooled with the next largest site with > 6 subjects. To break ties if more 
than one site has the same number of subjects, the site identifier will be used as a secondary sort 
key. 
6.3 Analysis populations 
The Enrolled Population includes all subjects screened into the study irrespective of whether 
they received the study medication. 
Three principal analysis populations are defined as follows: 
 Intent-to-treat (ITT), consisting of all randomized subjects. Subjects will be assigned 
for analysis according to the group to which they are randomized. 
 Modified intent-to-treat (mITT), consisting of all subjects in the ITT group who 
received at least one dose of study medication. Subjects will be assigned for analysis 
according to the group to which they are randomized. 
 Safety consisting of all subjects who received at least one dose of study medication. 
Subjects will be assigned for analysis according to treatment received. 
The principal analysis population for the analyses of demographics and baseline characteristics 
and efficacy will be the mITT population. Sensitivity analyses of the completion status 
endpoint will be carried out using the ITT population.  
 
Safety summaries will be provided for the Safety population.  
 
Data recorded on subjects who are in the ITT but not in the mITT or Safety populations will be 
included in data listings. 
6.4 Protocol Deviations 
All protocol deviations will be assessed and documented on a case-by-case basis prior to the 
database lock. A listing of protocol deviations will be provided within Appendix 16.2. 
 
6.5 Data Summaries 
The data will be summarized in tabular form by treatment group (2.4 mg Lofexidine, 3.2 mg 
Lofexidine and Placebo) and overall. In addition safety data will be summarized by treatment 
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group where the 2.4 mg Lofexidine and 3.2 mg Lofexidine doses are combined to form a single 
Lofexidine treatment group.  
 
For physical examination, when calculating the percentage reporting each category, the “Not 
Done” category will not be included in the denominator. 
 
Subject demographics and baseline characteristics will be presented for the mITT population.  
 
All safety data and protocol deviations will be presented for the safety population. 
 
Subject disposition will be summarized using the enrolled population.  
 
All efficacy variables will be assessed using the modified ITT population. 
Graphical presentations of the data will also be provided where appropriate. 
6.6 Disposition of Subjects 
The following will be summarized: 
 The number of subjects who enrolled into the study,  
 The number of enrolled subjects that failed to be randomized along with the reasons, 
 The number of enrolled subjects randomized, and 
 The number of randomized subjects that received at least one dose of study medication,  
 The number of randomized subjects that complete the double-blind and open-label 
phases.  
Reason for and timing of withdrawal will be summarized separately for the double-blind phase 
and the open-label phase. The reasons for withdrawal during the double-blind phase are 
classified as follows: 
 Lack of efficacy (i.e. Intolerable withdrawal symptoms) AE related to the study drug 
 AE related to study drug 
 Other reasons 
o AE unrelated to study drug or withdrawal (e.g. Concomitant illness) 
o There is evidence of contraband drug use while participating in the study 
o The subject requires therapy with an exclusionary drug 
o Lack of compliance with protocol and/or unit procedures 
o Other (e.g. Subject withdrew consent due to personal reasons) 
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The reasons for withdrawal during the open-label phase are classified as follows: 
 Lack of efficacy (i.e. Intolerable withdrawal symptoms) AE related to the study drug 
 AE related to study drug 
 Other reasons  
o AE unrelated to study drug or withdrawal (e.g. Concomitant illness) 
o The subject requires therapy with an exclusionary drug 
o Lack of compliance with protocol and/or unit procedures 
o The subject is Lost to Follow Up 
o Other (e.g. Subject withdrew consent due to personal reasons) 
For those subjects entering the open-label phase, the following will be tabulated 
 Which setting was the subject seen (inpatient, outpatient) 
 Primary reason for inpatient- setting 
o PI Clinical Discretion - Not AE  
o Standard of Care  
o Treatment of AE (but subject remains on study medication) 
o Indigent  
o Other 
 Primary reason for outpatient- setting 
o Subject Preference 
o Appropriate per PI Clinical Discretion  
o Standard of Care 
o Space Limitations at Site (Bed Availability) 
o Other  
6.7 Baseline Comparability 
6.7.1 Study Population 
Subject demographics and baseline characteristics will be presented for all subjects within the 
mITT population. 
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6.7.2 Variables Considered 
Standard continuous or categorical variable summaries will be presented for the following 
variables: 
Demography  
 
Site number 
 
Age at screening visit as recorded on the study database (years) 
 
Gender (Male, Female) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other). If more than one race is selected than 
categories will be created for the mixed race. 
 
Height (cm)  
 
Bodyweight (kg) 
 
BMI (kg/m2) calculated as weight (kg) divided by (height (m))2 rounded to one decimal 
place. 
Medical History  
Separate tabulations will be produced for previous and ongoing conditions with all conditions 
coded using MedDRA Version 16.0 (primary system organ class and preferred term). 
Smoking & Alcohol History  
 Ever smoked cigarettes (Yes, No). If yes, 
o Number of years used 
o Average number of times used/day 
o Whether currently smoking (Yes, No) 
 Ever used other tobacco products (Yes, No). If yes, whether used 
o Cigar 
o Chew 
o Snuff 
o Pipe 
 
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Alcohol History  
 Was Alcohol ever used? (Yes, No). If yes, 
o Number of years used alcohol was used (Yes, No)  
o Currently using (Yes, No) 
o Average number of times consumed/day 
Opioids Abuse  
(If for any subject, information is recorded within the obsolete opioids abuse screen and the 
concomitant medication screen, data recorded on the concomitant medication screen will take 
precedence) 
 Primary Opioid of Abuse 
 Duration of substance abuse (years). If a subject reports more than one drug the maximum 
duration reported will be used. 
 Time since last use of an opioid to date of informed consent (days) 
 Amount consumed per day (mg). If more than one drug is reported the cumulative mg use 
will be used. 
 Average number times taken per day. If more than one drug is reported the cumulative 
value will be taken. 
Infectious Disease Panel and Syphilis Tests at Screening  
 
Syphilis Antibody (Positive, Negative) 
 
HBsAg (Reactive, Non-reactive) 
 
Anti-HBc, Total (Reactive, Non-reactive) 
 
Hep B Surface Ab (IU/L) 
 
Anti-HCV (Reactive, Non-reactive) 
Urine Drug Screen at Screening  
 
Result, positive for: 
o 
Amphetamines (Yes, No) 
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o 
Methamphetamines (Yes, No) 
o 
Cocaine (Yes, No) 
o 
Barbiturates (Yes, No) 
o 
Opiates (Yes, No) 
o 
Benzodiazepines (Yes, No) 
o 
Cannabinoids (Yes, No) 
o 
Methadone (Yes, No) 
o 
Buprenorphine (Yes, No) 
Prior medications  
Verbatim terms (as recorded on the CRFs) of medications that ceased prior to the time of the 
initial dose of study medication will be mapped to Anatomical Therapeutic Chemical (ATC) 
Level 2 and Drug Reference Names using the World Health Organization (WHO) dictionary 
(Version 3.13 Enhanced). Prior medications will be listed in Appendix 16.2. 
6.8 Measurement of Treatment Compliance 
Each of the inpatient doses during Days 1-7 will be observed by the site staff. Following 
administration of the oral study medication, hand and mouth checks will be performed to 
ensure that the dose is swallowed. In an inpatient setting during Days 8-14, each dose will be 
observed by study staff and hand and mouth checks will be performed. In an outpatient setting 
during Days 8-14, self-dosing compliance will be evaluated by pill count and whether the dose 
has changed from the prior day and if so the reason for the change. Subjects will be instructed 
to call the physician’s office before taking the next dose of study medication if they notice any 
marked dizziness, especially when standing from a sitting or lying position. The physician will 
determine if the next dose should be delayed, skipped, or the subject should be seen. Any 
change in physician prescribed dosing will be noted in the study file and confirmed also by pill 
count and subject report at the next visit. Details of compliance will be tabulated. 
6.9 Primary Endpoint 
The primary efficacy endpoint is AUC based on SOWS-Gossop scores from Days 1 through 7. 
The study null hypothesis H0 and alternative hypothesis H1 are as follows: 
H0: There is no difference in the mean SOWS-Gossop AUC (1-7) between either of the 2.4 mg 
Lofexidine and 3.2 mg Lofexidine doses and placebo.   
H1: There is a difference in the mean SOWS-Gossop AUC (1-7) between either of the 2.4 mg 
Lofexidine and 3.2 mg Lofexidine doses and placebo.   
The null hypothesis H0 will be rejected in favor of H1 if there is evidence at the α = 5% 
significance level using a 2-sided test. Furthermore if H0 is rejected in favor of H1 and the mean 
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SOWS-Gossop AUC (1-7) is less for the Lofexidine dose in comparison to placebo then the 
Lofexidine dose for which there is evidence of a difference will be declared superior to placebo 
in the treatment of opioid withdrawal in adult patients with opioid dependence. 
 
6.9.1 Principal Analysis 
A pattern-mixture approach5, with subjects stratified by disposition within Days 1-7, will be 
used in assessing SOWS-Gossop AUC (1-7). The 4 disposition strata are as follows:  
 
 Subjects who complete Days 1-7 of the study (i.e. receives at least one dose of study 
medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop assessment 
on Day 7); 
 Subjects who discontinue due to lack of efficacy (including adverse events related to 
opioid withdrawal);  
 Subjects who discontinue due to adverse events related to intolerability or toxicity to 
study drug; and  
 Subjects who discontinue for other reasons.  
 
The inference is comprised of several steps. The first two rely on standard statistical software 
and a commonly-used type of statistical model. The remaining three rely on matrix 
manipulations. Additionally, the last step appeals to the statistical delta method (propagation of 
errors). 
 
1. Transformation. Because of the inherent skewness in the SOWS-Gossop scores the raw 
data will first be transformed to the natural logarithm of the score plus 1.0. 
2. Modelling. A linear mixed effects repeated-measures model will be constructed for the 
SOWS-Gossop score. The fixed effects will be disposition stratum, treatment and time, 
and their respective two-way and three-way interactions, as well as a main effect of 
gender (randomization stratification factor) and baseline (pre-dose) SOWS-Gossop 
score as a one degree of freedom covariate. For each combination of treatment and 
stratum, the time course will be modelled as a linear change point model, allowing for 
one slope between Days 1 and 2 and a possibly different slope from Days 2 through 7. 
The model will parameterized to ensure that the predictions from the two line segments 
agree at Day 2. Subjects will be treated as a random effect, and the slope and intercept 
parameters will be treated as random coefficients. Modelling the time course, rather 
than using each time point as a discrete level of a model factor, allows estimation of 
group means through Day 7 even in the non-completer strata. The choice of Day 2 as 
the change point is based on prior lofexidine studies, in which SOWS-Gossop mean 
scores in the placebo group increased from Day 1 to Day 2 and then decreased through 
Day 7. The modelling allows a different time course for each of the lofexidine dose 
groups. 
3. Point estimates of AUC (1-7). For each combination of disposition stratum, treatment 
and study day, the estimated least squares means SOWS-Gossop (on the log scale) for 
males and females will be combined using a weighted average, the weights being the 
relative proportions of males and females in the mITT population for each of the 12 
stratum. The results will then be transformed back to the original SOWS-Gossop scale 
of measurement, from which point estimates of AUC (1-7) for each combination of 
stratum and treatment will be computed using the linear trapezoidal rule. It should be 
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noted that these calculations will not be derived from AUC(1-7) computed within 
individual subjects, many of whom will have incomplete data for the later study days in 
Days 1-7. In particular, there will be no imputation of data for individual subjects. 
4. Estimates of treatment effect. For each active treatment, the treatment effect (lofexidine 
3.2 mg versus placebo or lofexidine 2.4 mg versus placebo) will be estimated with 
respect to AUC (1-7) within each disposition stratum. Then a weighted average of 
treatment effects will be computed, where the weights are the relative proportions of 
subjects in the 4 strata. 
5. Interval estimates of AUC (1-7) and hypothesis testing. The covariance matrix of the 
mixed model’s estimated fixed effects will be used with standard linear model methods 
to derive the covariance matrix of the weighted average of male and female log-
transformed SOWS-Gossop scores. The multivariate delta method (Ku, 1966; 
NIST/SEMATECH e-Handbook) will be used to derive the covariance matrix of the 
back-transformed SOWS-Gossop time course. Standard linear model methods will then 
be used to derive the covariance matrix of the weighted average of AUC (1-7) treatment 
effects, from which confidence intervals and p-values will be derived. 
 
6.9.2 Sensitivity Analysis 
The following sensitivity analyses will be conducted: 
 The loge (SOWS-Gossop score +1) from day 1 to day 7 will be analyzed using a mixed 
model repeated measures (MMRM) model.    
The model will include fixed effects for treatment group, baseline loge(SOWS-Gossop 
score +1), gender, visit (day 1, day 2 ,day 3, day 4,day 5, day 6 and day 7) and site 
(using the pooling algorithm detailed in section 6.2). In this model the treatment group 
term in the model represents the effect of treatment over days 1 to 7.  An unstructured 
covariance model will be used. However, in the event that this model does not converge 
then the following covariance models will be used in order until the model converges: 
Toeplitz, first-order autoregressive and compound symmetry.  Analysis will be 
performed using PROC MIXED in SAS and the resultant F-tests will be based on 
Kenward-Roger’s adjusted degrees of freedom. 
 The above MMRM analysis assumes that the missing data are missing at random 
(MAR). This analysis provides an unbiased estimate of the treatment effect that would 
have been observed had all subjects continued on treatment until day 7. It therefore 
assumes that the response for withdrawn subjects will follow the trajectory of the 
respective treatment after discontinuation. In order to assess the robustness of the results 
to the MAR assumption a sensitivity analysis will be conducted as follows under the 
assumption that the data are missing not at random (MNAR). Specifically, a pattern-
mixture model will be implemented, where it will be assumed that Lofexidine 
withdrawals will have a trajectory comparable to placebo post withdrawal. This analysis 
will therefore provide a stress test of the Missing at Random assumption of the 
conventional mixed model employed in the MMRM analysis. The pattern-mixture 
model will be implemented using multiple imputations (Ratitch6, 2011). This method is 
detailed in the section entitled “Pattern-Mixture Model with Control-Based Pattern 
Imputation” (Ratitch7, 2013).  Briefly, the initial step is to impute the relatively rare, 
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non-monotone missing data via the MCMC Option of SAS® PROC MI. This 
imputation model will include fixed effects for treatment, loge (SOWS-Gossop score 
+1) at each of the visits, gender and site.  The next step applies to the monotone missing 
data. The values for each pattern will be imputed using the chained equation method by 
SAS® PROC MI option MONOTONE REG. This MNAR imputation employs only the 
appropriate data for each pattern. That is, the missing data for Lofexidine treatment arm 
at time t will be imputed using only the data on placebo subjects up to time t and the 
data for Lofexidine subjects who have data up to time t-1 but are missing data at time t. 
The model for imputing missing data at time t will include fixed effect terms for loge 
(SOWS-Gossop score +1) from the baseline visit through to the t-1 visit, gender and 
site. Note that that a term for treatment group is not included in this imputation model as 
the imputation is based on placebo subjects with outcome data at time t. This process 
continues until the missing data are imputed for all time points. The imputed data sets 
will be analyzed with the same MMRM model employed in the sensitivity analysis 
described in the 1st bullet and then summarized using PROC MIANALYZE.  
 In a further sensitivity analysis a “tipping point analysis” (Ratitch7, 2013) will be 
conducted in order to understand the “tipping point” δ at which the conclusions change 
from being statistically significant at the α=5% level using a 2-sided test in favor of 
Lofexidine to not statistically significant. This sensitivity analysis as per the sensitivity 
analysis described above begins with an imputation of the non-monotone missing data 
using the MCMC option of Proc MI, based on standard MAR assumptions. Then all 
monotone missing values are imputed using standard MAR assumptions, except in the 
imputation model in this instance will also include a covariate for treatment. This is the 
start of the tipping point analysis (delta = 0). Delta is the adjustment that is added to the 
loge(SOWS-Gossop score +1) at each visit after dropout during imputation. This 
increment is only added to the missing visits for the Lofexidine group. Delta is 
gradually increased in increments of 1 until the point at which the comparison for the 
Lofexidine group to placebo loses statistical significance. (An increment of 1 is selected 
because the SOWS-Gossop scale ranges from its lowest to highest score by consecutive 
integers.) Effectively this analysis provides the amount by which the Lofexidine 
subjects who discontinued early would need to be worse at each visit for the null 
hypothesis of no treatment difference to no longer be rejected. The imputed datasets are 
analyzed with the same MMRM model used in the primary analysis. The results are 
analyzed using PROC MIANALYSE. 
 The studentized residuals will be assessed for normality using a histogram and quantile-
quantile plot. Other diagnostic tests may be performed following the inspection of data 
and potential outliers. If departure from normality or outliers are detected then non-
parametric analysis may be conducted. Full details will be provided within the final 
SAP prior to database lock.  These diagnostics will be performed for all ANCOVA and 
MMRM analyses specified within this SAP. 
 
6.9.3 Exploratory Analysis 
The 1st MMRM sensitivity analyses of the primary efficacy endpoint will be performed by the 
following key baseline characteristics: Age, gender, race (white or non-white) and baseline 
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loge(SOWS-Gossop score+1). For each key baseline characteristic, the main effect and 
treatment-by-subgroup interaction terms will be added to the linear mixed effects repeated-
measures model used in the primary endpoint analysis.  Any interactions that are statistically 
significant at the 10% level may have their nature described. This will be determined after the 
blind is broken.   
6.10 Secondary Endpoint 
The secondary efficacy endpoint is the completion status (i.e., whether a subject receives at 
least one dose of study medication on Day 7 and completes the 3.5-hour post-dose SOWS-
Gossop assessment on Day 7). The proportion of subjects in each treatment arm who receive at 
least one dose of study medication on Day 7 and complete the 3.5-hour post-dose SOWS-
Gossop assessment on Day 7 will be analyzed using a logistic regression model including fixed 
effects for treatment group, gender and site using the mITT population. One test will compare 
the 3.2 mg lofexidine group to placebo; a second will compare the 2.4 mg Lofexidine group to 
placebo. A sensitivity analysis will be performed on this endpoint using the ITT population. 
 
6.11 Tertiary/Exploratory Endpoints 
SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7 
An MMRM model will be used to test for a difference in the loge (SOWS-Gossop score +1) at 
each of days 1, 2, 3, 4, 5, 6, and 7 between the 3.2 mg Lofexidine group and placebo and 
between the 2.4 mg Lofexidine group and placebo. The model will include fixed effects for 
treatment group, baseline loge (SOWS-Gossop score +1), gender, visit (day 1, day 2, day 3, day 
4, day 5, day 6 and day 7), visit by treatment group interaction and site (using the pooling 
algorithm detailed in section 6.2). An unstructured covariance model will be used. However, in 
the event that this model does not converge then the following covariance matrix will be used 
in order until the model converges: Toeplitz, first-order autoregressive and compound 
symmetry.  Analysis will be performed using PROC MIXED in SAS and the resultant F-tests 
will be based on Kenward-Roger’s adjusted degrees of freedom. 
OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS 
The same methods used for SOWS-Gossop detailed above on days 1, 2, 3, 4, 5, 6, and 7 will be 
used for OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS scores on days 
1, 2, 3, 4, 5, 6, and 7. Depending on the distribution of these outcomes data transformations 
maybe used to normalise the data. Any transformation will be specified within the SAP prior to 
database lock.     
Mean treatment profiles will be presented for the following: 
 
SOWS-Gossop  
 
OOWS-Handelsman  
 
MCGI (Subject and Rater) 
 
VAS-E  
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 
COWS 
Retention Analysis (Time to Removal from Study Treatment) 
Time to removal from study treatment is defined as the last study day on which the subject 
received treatment. The time for subjects who complete some but not all treatment on Day 7 
will be Day 7, uncensored. Subjects who complete all treatments on Day 7 will be censored at 
Day 7. This endpoint will be summarized descriptively for each combination of treatment group 
and gender with Kaplan-Meier curves and tabulations of the number and percentage of subjects 
newly removed from receiving study treatment on each of study Days 1 to 7. Each Lofexidine 
dose group will be compared inferentially to placebo with a Cox proportional hazards 
regression model of time to removal from study, including covariates for treatment, gender and 
site. If the Cox proportional hazards model does not converge, then the covariates gender and 
site will be dropped from the model and the Cox proportional hazards regression model will be 
stratified by gender and site instead. The estimated hazards ratio will be reported as a 
descriptive measure along with the associated 95% confidence interval. 
Concomitant Medication Analysis 
For each of Days 1 to 7, each subject’s number of concomitant medication taken will be treated 
as a continuous variable. Descriptive statistics will be provided on the as-observed data on each 
study day and also overall study days.  
Status of Detoxification on Day 7 or Early Termination as Assessed by the Site Investigator 
Descriptive statistics (numbers and percentages) on the status of detoxification 
(successful/unsuccessful) as assessed by the Site Investigator at Day 7 or early termination will 
be presented by treatment group overall and by gender within treatment group. 
COWS AUC (1-7) 
COWS AUC (1-7) will also be analyzed using a modelling approach analogous to the 
modelling of SOWS-Gossop AUC (1-7). While the functional form of the time course for 
SOWS-Gossop is based on historical data, the functional form of the time course for COWS 
will be based on the data from this study. 
In addition, COWS will be analyzed using a mixed model repeated measures (MMRM) model 
in the same way as detailed for the sensitivity analysis of  the primary endpoint with baseline 
COWS (based on same functional form for primary analysis) as a covariate. 
Assessment of effectiveness 
Summary statistics will be provided by treatment day (overall and by gender) over days 8-14 
(Open Label Phase): 
 
SOWS-Gossop  
 
OOWS-Handelsman  
 
MCGI (Subject and Rater)  
 
VAS-E  
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 
COWS  
In addition, the following will be summarized overall and by gender over Days 8-14: 
 
Number and proportion of subjects successfully completing detoxification and the 
number of days required to complete detoxification as assessed by the Site Investigator. 
6.12 Multiplicity 
For the primary and secondary endpoints, the treatment comparisons subject to control of the 
false positive rate will be 3.2 mg lofexidine vs. placebo and 2.4 mg lofexidine vs. placebo. 
Comparisons of 3.2 mg vs. 2.4 mg will be descriptive.  The familywise error rate (FWE) for the 
collection of primary and secondary endpoint comparisons will be controlled at the 0.05 level, 
two-sided, by a sequential testing strategy in which hypotheses are tested  in the following 
order, each at the 0.05 level, using a two-sided test. 
1. Primary: AUC(1-7), 3.2 mg lofexidine versus placebo; 
2. Primary: AUC(1-7), 2.4 mg lofexidine versus placebo; 
3. Secondary: Completion rate, 3.2 mg lofexidine versus placebo; and 
4. Secondary: Completion rate, 2.4 mg lofexidine versus placebo. 
The tertiary/exploratory endpoints will be tested without multiplicity adjustment. 
6.13 Safety analysis 
All subjects who receive at least dose one of study medication will be included in the analysis 
of safety. 
Safety measures will be summarized for the following subject cohorts for the open label phase: 
 All treated subjects; 
 Treated subjects without urinary evidence of illicit drug use; and 
 Treated subjects with urinary evidence of illicit drug use (may be further subdivided by 
type of illicit drug used). 
Safety measures will only be summarized for all treated subjects for the double blind phase. 
Extent of exposure 
Extent of exposure will be described by whether the subject took the trial medication and the 
number of days exposure to double-blind study medication (last date of double-blind 
medication minus first date of double-blind medication + 1). Average daily dose of double-
blind study medication will also be calculated. Exposure to open-label medication will also be 
calculated as last date of open-label medication – first date of open-label medication + 1. No 
allowance will be made for breaks in therapy in the exposure calculations. Average daily dose 
of open-label study medication will also be calculated.  If the date of last dosing is completely 
missing for the trial medication then the date of last dosing will be taken for analysis purposes 
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as the date the medication was last dispensed.  If only the month of the last dose is recorded, the 
first day of the month will be assumed as the last dosing date. 
Adverse Events During the Double-Blind Phase of the Study 
All AEs will be listed and tabulated by severity, relationship to study medication, primary 
system organ class and preferred term according to MedDRA Version 16.0.  In counting the 
number of events reported, a continuous event, i.e., an event reported more than once and 
which did not cease, will be counted only once with the worst recorded severity; non-
continuous AEs reported several times by the same subject will be counted as multiple events.  
Events present immediately prior to the first dose of study medication that do not worsen in 
severity, will not be regarded as treatment emergent.  Events with start dates more than 30 days 
after the administration of the last dose of study medication will not be considered treatment 
emergent and will be listed separately.  In deriving the tabulation relating to preferred term 
reporting, the severity of a recurrent AE will be taken to be the most severe and the relationship 
to study medication as the highest probable.   
The following will be summarized and presented for the overall population and by treatment 
group: 
 The number and percentage of subjects experiencing at least 1 treatment emergent 
TEAE by MedDRA preferred term and SOC. A chi-squared test will be used to test for 
a difference in the percentage of subjects experiencing at least 1 TEAE between each of 
the 2 Lofexidine doses and placebo. 
 The number and percentage of subjects experiencing an opioid withdrawal related 
TEAE by MedDRA preferred term and SOC. 
 The number and percentage of subjects experiencing TEAEs by severity of event 
 The number and percentage of subjects experiencing TEAEs by relationship to IP 
 The number and percentage of subjects experiencing treatment-related adverse events 
(i.e. Possibly Related, Probably Related, Definitely Related) 
 The number and percentage of subjects experiencing at least 1 treatment emergent SAE 
by MedDRA preferred term and SOC  
 The number and percentage of subjects experiencing SAEs by severity of the event  
 The number and percentage of subjects experiencing SAEs by relatedness to IP 
Adverse events whilst receiving Lofexidine therapy during the open-label phase  
All AEs reported whilst receiving Lofexidine therapy will be listed and tabulated by treatment, 
severity, relationship to study medication, primary system organ class and preferred term 
according to Version 16.0 of MedDRA.  In counting the number of events reported, a 
continuous event, i.e., an event reported more than once and which did not cease, will be 
counted only once with the worst recorded severity; non-continuous AEs reported several times 
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by the same subject will be counted as multiple events.  Events present immediately prior to the 
first dose of Lofexidine during the open-label phase that do not worsen in severity, will not be 
regarded as treatment emergent.  Events with start dates more than 30 days after the 
administration of the last dose of Lofexidine will not be considered treatment emergent and will 
be listed separately.  In deriving the tabulation relating to preferred term reporting, the severity 
of a recurrent AE will be taken to be the most severe and the relationship to study medication as 
the most probable.   
For data analysis purposes, all TEAEs for which data are missing regarding assessments of 
relatedness and/or severity will be defaulted to be assessed as being related and at the highest 
severity grade, respectively. Missing or incomplete TEAE start dates will be imputed to 
correspond with the date of dosing.  
Narratives of deaths, serious and other significant adverse events will be provided in the 
relevant section of the CSR. 
A complete subject listing of all adverse events will be provided in Appendix 16.2 to the study 
report. This listing will include treatment, AE verbatim, MedDRA primary system organ class 
and preferred term, the time of onset and cessation of event relative to first dosing of study 
medication, duration of AE (for ongoing AEs use the date of investigator signature as the 
cessation date for calculation purposes), whether serious, severity, relationship to study 
medication, action taken and outcome. 
Treatment emergent and non-treatment emergent events will be listed separately. 
Clinical Laboratory Evaluations 
Descriptive statistics will be calculated for the last double-blind and last open-phase post-
baseline assessment as well as changes from baseline for each hematology, coagulation and 
chemistry variable. Each measurement will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range 
from screening to each follow-up visit will be presented. 
Descriptive statistics for urinalysis will be calculated for the last double-blind and last open-
phase post-baseline assessment as well as changes from baseline. 
Details of microscopic urinalysis will be provided in Appendix 16.2 of the report.  
Vital Signs During the Double-Blind Phase 
Vital signs (blood pressure and pulse [sitting or recumbent and standing], respiration, and 
temperature) will be measured at screening, baseline and before each dose and 3.5 hours after 
each dose (with the exception of the dose taken at 11 PM, where the measurement at 3.5 hours 
post-dose will not be done) during the double-blind phase. Summary statistics for observed and 
changes from baseline will be tabulated at each follow-up for each vital sign parameter and at 
post-baseline double-blind endpoint for each variable.  
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In addition the number and proportion of subjects having: 
 Systolic blood pressure ≥180mmHg and an increase of ≥ 20mmHg from baseline 
 Systolic blood pressure ≤ 90mmHg and a decrease ≥ 20mmHg from baseline 
 Diastolic blood pressure ≥ 105mmHg and an increase ≥ 15mmHg from baseline 
 Diastolic blood pressure ≤ 50mmHg and a decrease ≥ 15mmHg from baseline 
will be summarized at each follow-up visits.  
Vital Signs During the Open-Label Phase 
Vital signs (blood pressure and pulse [sitting or recumbent and standing]) will be assessed for 
one dose every day at pre-dose and 3.5 hours post-dose on Days 8-13, with vital signs measured 
once pre-dose on Day 14. Summary statistics for observed and changes from baseline will be 
tabulated at each follow-up and at post-baseline open-phase endpoint for each variable. 
Mean profiles by treatment will be presented for sitting and standing blood pressure and heart 
rate. 
ECG  
ECG data collected during the double-blind and open-label phase will be analyzed separately in 
a stand-alone report.   
In addition, PI overall interpretation of the ECG (Normal, Abnormal NCS, and Abnormal CS) 
will be listed in Appendix 16.2. 
C-SSRS 
The following will be summarized and analyzed separately for the double blind and open label 
study phases: 
1. To assess safety: 
a. Suicidality: The number and percentage of subjects reporting any suicidal 
ideation or behavior throughout the assessment period.   
b. Suicidal behavior only: The number and percentage of subjects reporting any 
type of suicidal behavior throughout assessment period.  
c. Suicidal ideation only: The number and percentage of subjects reporting any 
type of suicidal ideation throughout assessment period.  
In addition, taking into account baseline data regarding suicidal ideation to determine if 
suicidal ideation or behavior has worsened: 
d. Emergence of suicidal ideation: The number and percentage of subjects 
reporting no suicidal ideation at baseline and any type of ideation during the 
assessment period.   
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e. Emergence of serious suicidal ideation: The number and percentage of 
subjects reporting no suicidal ideation at baseline and had serious suicidal 
ideation (as defined above; score of 4 or 5 on suicidal ideation severity rating) 
during the assessment period.   
f. Worsening of suicidal ideation: The number and percentage of subjects whose 
most severe suicidal ideation rating is more severe than it was at baseline.  
g. Emergence of suicidal behavior: The number and percentage of subjects who 
had no suicidal behavior at baseline and any type of behavior during the 
assessment period.  
For each of the above endpoints a-g, Fisher’s Exact test will be used to test for a difference 
between the 2 Lofexidine treatment groups and placebo during the double blind phase only. 
Physical Examination 
The body systems within the physical examination data at screening, baseline (day 1), day 7 
and end of the study will be summarized by treatment (Normal; Abnormal NCS, Abnormal 
CS).  The changes from baseline to end of the study in bodyweight will also be tabulated. 
Concomitant medications 
Concomitant medication verbatim terms (as recorded on the CRFs) after the initial dose of 
study drug will be mapped to Anatomical Therapeutic Chemical (ATC) Level 2 and Drug 
Reference Names using the World Health Organization (WHO) dictionary (Version 3.13 
Enhanced) and tabulated by treatment group and overall. 
Psychosocial Therapy Sessions  
 Whether subject received or participated in Psychosocial Therapy Sessions during the 
double blind phase (Yes, No). If yes, whether received the following 
o Group Counselling Session (Yes, No) 
o Art or Music therapy (Yes, No) 
o 12-Step Program Participation (Yes, No) 
o Other (Yes, No) 
Details of the Day 30 Follow-Up  
 Lost to Follow-up 
 Whether subject successfully entered one of the following programs: 
o None 
o Methadone 
o Buprenorphine 
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o Naltrexone 
o Other 
 Whether subject relapsed to drug use after exiting the study (Yes, No) 
6.14 Change to Planned Protocol Analysis 
The following changes have been made to the planned protocol analyses sections: 
Section 17.2.7 Control of the False Positive Rate and Statistical Testing Strategy  
Change: All statistical tests will be two-sided at the 0.05 significance level. This is a change 
from the protocol, where it was specified that statistical tests would be one-sided at the 0.025 
significance level.    
Reason: Two-sided statistical tests at the 0.05 significance level is statistical convention for 
hypothesis testing. 
Section 17.2.8.1 SOWS-Gossop AUC (1-7) 
Change: A number of sensitivity analyses have been added and are detailed in section 16.9.2 of 
the statistical analysis plan.  
Reason: To provide additional sensitivity analyses of loge (SOWS-Gossop score +1) from day 1 
to day 7 under differing mechanisms for missing data, including Missing at Random (MAR) 
and Missing Not at Random (MNAR)  
Section 17.2.8.2 Completion Status 
Change: A logistic regression model including fixed effects for treatment group, gender and site 
will be used instead of a Cochran-Mantel Haenszel test to test for a difference in completion 
status between the 2 Lofexidine groups and placebo. 
Reason: To additionally adjust for site in the analysis and to provide an interpretation of the 
effect of treatment using odds ratios. 
Sections: 17.2.8.3 SOWS-Gossop on Days 1, 2, 3, 5, 6 and 7 and 17.2.8.4 OOWS-
Handelsman, MCGI (Subject and Rater), VAS-E, and COWS 
Change: A MMRM model will be used to test for a difference in the loge (SOWS-Gossop score 
+1) at each of days 1 through 7 between the 2 Lofexidine groups and placebo. This replaces 
planned pattern-mixture approach used in the principal analysis. 
Reason: MMRM model is a standard approach for the analysis of treatment differences at 
different time points when there are repeated measures. 
17.2.8.5 Retention Analysis (Time to Removal from Study Treatment) 
Change: Gender will be included in the Cox proportional hazards regression model as covariate 
rather than stratifying Cox analysis by gender. In addition site will also be included in the 
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model. The confidence intervals for the hazard rations will also be two-tailed rather than one-
tailed as specified within the protocol. 
Reason: To ensure the modelling and presentation of confidence intervals is consistent with 
other multivariate statistical models specified within the statistical analysis plan. 
  
7. REFERENCES 
(1) 
Bazett HC. An analysis of time relations of the electrocardiogram. Heart 1920; 7: 353-
370.3. 
(2) 
Fridericia LS. Die systolendauer in elektrokardio-gram bei normalen menschen und bei 
herzkranken. Acta Med Scand 1920; 53: 469. 
(3) 
SAS Institute Inc.  The SAS System, Version 9.3.  Cary, NC, SAS Institute Inc. 2012. 
(4) 
ICH E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential for Non-Antiarrhythmic Drugs. 
(5) 
Little RJA. Pattern-mixture models for multivariate incomplete data. Journal of the 
American Statistical Association 1993;88:125-134. 
(6) 
Ratitch B and O’Kelly M. Implementation of Pattern Mixture Models Using Standard 
SAS/STAT Procedures. PharmaSug 2011 paper SP04. 
(7) 
Ratitch B and O’Kelly M. Missing Data in Clinical Trials: from Clinical Assumptions to 
Statistical Analysis using Pattern Mixture Models. Pharmaceutical Statistics 2013: 
DOI:10.1002/pst.1549. 
 
 
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Approval for implementation of 
Statistical Analysis Plan 
 
Title: 
A Phase 3, Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Efficacy, Safety, and Dose-Response 
Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable 
Dose Lofexidine Treatment (Days 8-14) 
 
 
 
 
Reference: 
USWM-LX1-3003-1/SAP 
 
 
 
 
Version: 
1.0 
 
 
 
 
Date effective: 
18-JUN-14 
 
 
 
 
Author: 
 
 
 
reviewer: 
 
 
 
Author’s signature: 
 
 Date:  
 
Reviewer’s signature: 
 
 Date:  
 
 
 
 
 
 
 
 
The above Statistical Analysis Plan has been reviewed and approved by the Sponsor: 
 
 
  
 
Name of Approver: 
 
  
 
 
 
  
 
Position: 
Medical Director, US WorldMeds, LLC   
 
 
 
  
 
Signature for 
 
 Date: 
 
 
 
  
 
Name of Approver: 
 
  
 
 
 
  
 
Position: 
Sr. Manager, Biometrics,  US WorldMeds, LLC 
  
 
 
 
  
 
Signature for 
 
 Date: 
 
 
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Statistical Analysis Plan Addendum 1 
Version: Final 
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STATISTICAL ANALYSIS PLAN  
ADDENDUM 1 
 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine 
Treatment (Days 8-14) 
Protocol Ref: USWM-LX1-3003-1 
Date effective: 24-Dec-2014 
 
 
 
 
 
 
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SUMMARY OF SECTIONS 
 
1 
INTRODUCTION 
 
 
 
 
 
 
 
 
2 
CHANGES TO EXISTING ANALYSIS PLAN 
 
 
 
 
 
 
 
3 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
 
 
 
 
 
 
 
4 
APPENDIX 16.2 LISTINGS 
 
 
 
 
 
 
 
 
 
 
 
 
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1. INTRODUCTION 
 
This document is an addendum to the statistical analysis plan dated 18th June 2014 for the 
analysis of the US WorldMeds, LLC study USWM-LX1-3003-1. 
 
All decisions were taken prior to database lock. 
2. CHANGES TO EXISTING ANALYSIS PLAN 
Change 1 
 
Section 6.1 General 
 
Add following sentence 
 
For all statistical models analyzed via log-transformed data the back-transformed LS 
means will be presented in the output.  
 
Change 2 
Section 6.2 Derived Data 
Site Pooling for Statistical Analysis 
The following text was removed: 
For the purposes of statistical analyses models where site is included within the model as a fixed 
effect, sites randomizing < 6 subjects will be pooled from smallest to largest until the pooled site 
subsequently created has at least 6 subjects. In the event that the pooling of sites with less than 6 
subjects does not result in a site with > 6 subjects, then that pooled site with < 6 subjects will 
also be pooled with the next largest site with > 6 subjects. To break ties if more than one site has 
the same number of subjects, the site identifier will be used as a secondary sort key. 
Justification 
 
The primary analysis no longer includes site in the model; therefore site has been removed as a 
variable from all subsequent statistical models.   
 
 
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Change 3 
 
Section 6.3 Analysis Populations 
 
An additional population has been added 
 
The per-protocol population. This analysis set will be a subset of the mITT population and will 
consist of all subjects who satisfy all of the inclusion/exclusion criteria and who correctly receive 
the treatment to which they are randomized and do not have a major protocol deviation within 
the double-blind phase. The selection of subjects for the per-protocol population will be made 
prior to database lock.  Major protocol deviation will be broadly classified into five main 
categories based on ICH Harmonised Tripartite Guideline Structure and Content of Clinical 
Study Reports E3:  
1. those patients who enter the study despite not satisfying entry criteria 
2. those patients who developed non-safety related withdrawal criteria during the study and 
were not withdrawn 
3. those patients who received the wrong treatment 
4. those patients who received an excluded concomitant treatment, defined as any drug that 
is not included in the approved list of medications (as outlined in Appendix 16.2.2) or 
any antibiotic 
5. lack of major compliance with the protocol.  
The only variable to be assessed using the per-protocol analysis set will be the primary efficacy 
endpoint. 
Justification 
Due to the identification of some subjects taking prohibited medication during the double-blind 
period; a per-protocol population has been added to conduct a sensitivity analysis on the primary 
endpoint.  
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Change 4 
 
Section 6.7.2 Variables Considered 
 
Medical History 
Add the text in bold  
Separate tabulations will be produced for previous and ongoing conditions with all conditions 
coded using MedDRA Version 16.0 (primary system organ class and preferred term). An 
ongoing condition is defined as any history with any of the following 
≠ 
Marked as ongoing 
≠ 
With a missing stop date and ongoing not checked 
≠ 
Or a stop date after the first dose of study medication.   
Justification 
 
To make the definition clearer of what constitutes an ongoing condition.  
 
 
Change 5 
 
Section 6.7.2 Variables Considered 
 
 
Infectious Disease Panel and Syphilis Tests at Screening  
≠ 
HBsAg (Reactive, Non-reactive) 
Amend to 
 
≠ 
HBsAg (Confirmed Positive, Non-reactive) 
Justification 
 
Changed due to how the data is actually recorded on the laboratory vendor file. 
 
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Change 6 
  
Section 6.9 Primary Endpoint 
 
Amend to 
 
The primary efficacy endpoint is the difference between the overall LS means from a pattern 
mixture model based on log-transformed SOWS-Gossop scores from Days 1 through 7. 
The study null hypothesis H0 and alternative hypothesis H1 are as follows: 
H0: There is no difference in the overall means in log-transformed SOWS-Gossop scores from 
Days 1 through 7 between either of the 2.4 mg lofexidine and 3.2 mg lofexidine doses and 
placebo.   
H1: There is a difference in the overall means in log-transformed SOWS-Gossop scores from 
Days 1 through 7 between either of the 2.4 mg lofexidine and 3.2 mg lofexidine doses and 
placebo.   
The null hypothesis H0 will be rejected in favor of H1 if there is evidence at the α = 5% 
significance level using a 2-sided test. Furthermore if H0 is rejected in favor of H1 and the overall 
LS mean is less for the lofexidine dose in comparison to placebo, then any lofexidine dose for 
which there is evidence of a difference will be declared superior to placebo in the treatment of 
opioid withdrawal in adult patients with opioid dependence. To account for multiplicity of 
statistical hypothesis testing of two lofexidine doses, statistical significance of the comparison of 
high dose lofexidine to placebo must be established, before significance of the comparison of 
low dose lofexidine to placebo can be claimed. 
Justification 
 
The primary efficacy endpoint has changed from the area under the curve (AUC) from Days 1 to 
7 of the SOWS-Gossop scores to the overall (i.e., averaged over study Days 1 through 7) least 
squares (LS) means from a pattern mixture model based on log-transformed SOWS-Gossop 
scores from Days 1 through 7. The new endpoint stems from a revision of the pattern mixture 
model that incorporates comments on the modeling approach from the US Food and Drug 
Administration (FDA) in relation to patients who discontinue treatment.   
Using the proposed pattern mixture model, the combined process of imputation followed by 
MMRM does not assume MAR and provides an unbiased estimate of the treatment effect that 
follows under the assumption that the mechanism by which data are missing not at random 
(MNAR) is that upon withdrawal from the study, the SOWS-Gossop trajectory of subjects 
randomized to lofexidine evolves as the trajectory of placebo subjects. Thus, by assigning an 
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unfavorable placebo trajectory to patients who discontinue lofexidine treatment, the proposed 
model has addressed this concern. The nature of these changes is described in Change 7, 
following. 
 
Change 7 
 
Section 6.9.1 Principal Analysis 
 
Amend to 
 
A pattern-mixture approach5 will be used in assessing SOWS-Gossop from Days 1 to 7 inclusive 
using the mITT population. 
  
It will be assumed that subjects randomized to lofexidine who withdraw from the study will have 
a time trajectory comparable to placebo post withdrawal. The pattern-mixture model will be 
implemented using multiple imputations (Ratitch6, 2011). The imputation of missing values and 
the analysis will be performed multiple times (20 imputed datasets) with the initial seed value set 
at ‘123’, and the inference of this sensitivity analysis will be based on the combined estimates 
using the standard multiple imputation technique.This method is detailed in the section entitled 
“Pattern-Mixture Model with Control-Based Pattern Imputation” (Ratitch7, 2013).  Briefly, the 
initial step is to impute the relatively rare, non-monotone missing data via the MCMC Option of 
SAS® PROC MI. This step uses iterative methods, with which non-convergence is a possibility; 
should an MCMC imputation step not converge, additional imputations will be performed, and 
the first 20 MCMC imputations that converge will be used in the analysis. This imputation model 
will be implemented for each combination of gender and treatment. (It should be noted that by 
performing the imputation for each such combination, the imputation modelling will be richer 
than the model used to inferentially analyse the data. It is acceptable, even preferable, for the 
imputation model to be richer than for the analysis model (see Little and Rubin, 2002).   
The next step applies to the monotone missing data. The values for each pattern will be imputed 
using the chained equation method by SAS® PROC MI option MONOTONE REG. This MNAR 
imputation employs only the appropriate data for each pattern. That is, the missing data for 
lofexidine treatment arm at time t will be imputed using only the data on placebo subjects up to 
time t and the data for lofexidine subjects who have data up to time t-1 but are missing data at 
time t. The model for imputing missing data at time t will include fixed effect terms for study 
day from the baseline visit through to the t-1 visit and sex. Note that a term for treatment group is 
not included in this imputation model. This process continues until the missing data are imputed 
for all time points. The imputed data sets will be analyzed using the MMRM model described 
below and then summarized using PROC MIANALYZE. The model will include fixed effects 
for treatment group, baseline loge (SOWS-Gossop score +1), sex, study day (days 1-7), and 
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treatment group-by-day interaction. In this model the treatment group term in the model 
represents the effect of treatment over days 1 to 7.  An unstructured covariance model will be 
used. However, in the event that this model does not converge then the following covariance 
models will be used in order until the model converges: Toeplitz, first-order autoregressive and 
compound symmetry.  Analysis will be performed using PROC MIXED in SAS and the resultant 
F-tests will be based on Kenward-Roger’s adjusted degrees of freedom. 
Justification 
 
Fitting an MMRM analysis without the imputation described above would have entailed an 
assumption that the missing data are missing at random (MAR). The combined process of 
imputation followed by MMRM does not assume MAR and provides an unbiased estimate of the 
treatment effect that follows under the assumption that the mechanism by which data are missing 
not at random (MNAR) is that upon withdrawal from the study, the SOWS-Gossop trajectory of 
subjects randomized to lofexidine evolves as the trajectory of placebo subjects. 
 
Change 8 
 
Section 6.9.1 Sensitivity Analysis 
 
The text in bold has been edited: 
 
The following sensitivity analyses will be conducted: 
≠ The above analysis will be performed using the per-protocol population. 
≠ The loge (SOWS-Gossop score plus 1) from day 1 to day 7 will be analyzed using a 
MMRM model on the mITT population.    
The model will include fixed effects for treatment group, baseline loge (SOWS-Gossop 
score plus 1), sex, study day (days 1-7) and treatment group-by-day interaction. In this 
model the treatment group term in the model represents the effect of treatment over days 
1 to 7.  An unstructured covariance model will be used. However, in the event that this 
model does not converge then the following covariance models will be used in order until 
the model converges: Toeplitz, first-order autoregressive and compound symmetry.  
Analysis will be performed using PROC MIXED in SAS and the resultant F-tests will be 
based on Kenward-Roger’s adjusted degrees of freedom. This MMRM analysis assumes 
that the missing data are missing at random (MAR). This analysis provides an unbiased 
estimate of the treatment effect that would have been observed had all subjects continued 
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on treatment until day 7. It therefore assumes that the response for withdrawn subjects 
would have followed the trajectory of the respective treatment after discontinuation, had 
they not withdrawn.  
≠ In a further sensitivity analysis on the mITT population a “tipping point analysis” 
(Ratitch7, 2013) will be conducted in order to understand the “tipping point” δ at which 
the conclusions change from being statistically significant at the α=5% level using a 2-
sided test in favor of lofexidine to not statistically significant. This sensitivity analysis 
as per the sensitivity analysis described above begins with an imputation of the 
relatively rare non-monotone missing data using the MCMC option of PROC MI, 
based on standard MAR assumptions. The random seed for this set of analyses will 
be ‘456’. Then several analyses will be performed, indexed by the value δ, in each of 
which all monotone missing values are imputed using standard MAR assumptions, 
except in the imputation model in this instance will also include a covariate for 
treatment. In the first such analysis δ = 0, which effectively is last observation carried 
forward. In general, δ is the adjustment that is added to the loge (SOWS-Gossop score 
+1) at each visit after dropout during imputation. This increment is only added to the 
missing visits for the lofexidine groups. Delta is increased in increments of 1 (on the 
original SOWS-Gossop scale, before log transformation) until the point at which the 
comparison for the lofexidine group to placebo loses statistical significance. (An 
increment of 1 is selected, because the SOWS-Gossop scale ranges from its lowest to 
highest score by consecutive integers.) Effectively this analysis provides the amount by 
which the lofexidine subjects who discontinued early would need to be worse at each 
visit for the null hypothesis of no treatment difference to no longer be rejected. The 
imputed datasets are analyzed with the same MMRM model used in the primary analysis. 
The results are analyzed using PROC MIANALYZE. 
≠ The studentized residuals will be assessed for normality using a histogram and quantile-
quantile plot. Other diagnostic tests may be performed following the inspection of data 
and potential outliers. If departures from normality or outliers are detected then non-
parametric analysis may be conducted. Full details will be provided within the final SAP 
prior to database lock.  These diagnostics will be performed for all ANCOVA and 
MMRM analyses specified within this SAP. 
 
Justification 
As a result of changes made to the principal statistical analysis (Change 7 annotated, Section 
6.9.1) of the primary endpoint, the planed sensitivity analyses also required modification. 
Further, a per-protocol analysis of the primary endpoint was added due to the number of reported 
major protocol deviations. 
 
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Change 9 
Section 6.10 Secondary Endpoint 
The following text was amended: 
The secondary efficacy endpoint is the completion status (i.e., whether a subject receives at least 
one dose of study medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7). The proportion of subjects in each treatment arm who receive at least 
one dose of study medication on Day 7 and complete the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7 will be analyzed using a logistic regression model including fixed 
effects for treatment group and gender using the mITT population. One test will compare 
the 3.2 mg lofexidine group to placebo; a second will compare the 2.4 mg Lofexidine group to 
placebo. A sensitivity analysis will be performed on this endpoint using the ITT population. 
 
Justification 
 
Site has been removed as a variable from all statistical models.  All references for site will be 
removed from the statistical analysis plan where previously included in statistical models. 
 
Change 10 
 
 
Section 6.11 Tertiary/Exploratory Endpoints 
 
Amend the following text related to SOWS-Gossop on Days 1, 2, 3, 4, 5, 6, and 7 
An MMRM model will be used to test for a difference in the loge (SOWS-Gossop score +1) at 
each of days 1, 2, 3, 4, 5, 6, and 7 between the 3.2 mg Lofexidine group and placebo and 
between the 2.4 mg Lofexidine group and placebo. The model will include fixed effects for 
treatment group, baseline loge (SOWS-Gossop score +1), sex, visit (day 1, day 2, day 3, day 
4, day 5, day 6 and day 7) and treatment-by-visit interaction. An unstructured covariance 
model will be used. However, in the event that this model does not converge then the following 
covariance matrix will be used in order until the model converges: Toeplitz, first-order 
autoregressive and compound symmetry.  Analysis will be performed using PROC MIXED in 
SAS and the resultant F-tests will be based on Kenward-Roger’s adjusted degrees of freedom. 
 
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Justification 
 
The primary analysis no longer includes site in the model; therefore site has been removed as a 
variable from all subsequent statistical models.   
 
 
Change 11 
 
 
Section 6.11 Tertiary/Exploratory Endpoints 
 
Amend the following text related to OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, 
and COWS 
 
The same methods used for SOWS-Gossop detailed above on days 1, 2, 3, 4, 5, 6, and 7 will be 
used for OOWS-Handelsman, MCGI (Subject and Rater), VAS-E, and COWS scores on days 1, 
2, 3, 4, 5, 6, and 7. Depending on the distribution of these outcomes data transformations maybe 
used to normalise the data. Any transformation will be specified within the SAP prior to database 
lock.     
 
The text in bold was added to the following: 
 
The same methods used for SOWS-Gossop detailed above on days 1, 2, 3, 4, 5, 6, and 7 will be 
used for OOWS-Handelsman, MCGI (Subject [Severity of opiate withdrawal and side effect 
index separately] and Rater [Severity of illness and side effect index separately], VAS-E, and 
COWS scores on days 1, 2, 3, 4, 5, 6, and 7, where the baseline covariate will be the baseline 
value of the endpoint under analysis. The same model will be used for MCGI [Subject and 
Rater] and VAS-E, except that there will be no baseline covariate as these endpoints do not 
have a baseline measurement. Depending on the distribution of these outcomes data 
transformations maybe used to normalise the data. Any transformation will be specified within 
the SAP prior to database lock.     
 
Justification 
 
Certain efficacy variables are not measured at baseline. The MCGI Subject and Rater scales are 
each sub-divided into two components. 
  
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Change 12 
 
 
Section 6.11 Tertiary/Exploratory Endpoints 
The text in bold was amended for Retention Analysis (Time to Removal from Study Treatment): 
Time to removal from study treatment is defined as the last study day on which the subject 
received treatment. A completer for the purpose of this analysis is defined as a subject 
receiving at least 1 dose on Day 7 and the having the SOWS assessment completed.  This 
will be based on the flag indicating the subject completed the double-blind phase as 
recorded on the CRF. The time to removal from study treatment for completers will be 
censored on Day 7. The time to removal from study treatment for subjects who complete some 
treatment on Day 7 but who do not satisfy the definition of completer will be Day 7, uncensored.  
This endpoint will be summarized descriptively for each combination of treatment group and 
gender with Kaplan-Meier curves and tabulations of the number and percentage of subjects 
newly removed from receiving study treatment on each of study Days 1 to 7. Each Lofexidine 
dose group will be compared inferentially to placebo with a Cox proportional hazards 
regression model of time to removal from study, including covariates for treatment and 
sex. If the Cox proportional hazards model does not converge, then the covariate sex will be 
dropped from the model and the Cox proportional hazards regression model will be 
stratified by sex instead. The estimated hazards ratio will be reported as a descriptive 
measure along with the associated 95% confidence interval. 
 
Justification 
 
To make the definition clearer of what constitutes a completer for this analysis and to redefine 
the censoring algorithm accordingly.  The primary analysis no longer includes site in the model; 
therefore site has been removed as a variable from all subsequent statistical models.   
 
Change 13 
Section 6.11 Tertiary/Exploratory Endpoints 
The text in bold was added. 
Concomitant Medication Analysis 
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For each of Days 1 to 7, each subject’s number of concomitant medication taken will be treated 
as a continuous variable. Descriptive statistics will be provided on the as-observed data on each 
study day and also overall study days.  
Only days when the patient was taking active treatment will be considered. Days after 
active administration will be disregarded. 
For the calculation of the daily number of medications taken, the number of distinct coded 
drug names via the WHO dictionary will be used rather than verbatim terms. 
Justification 
 
To make the definitions within this analysis clearer.  
 
Change 14 
Section 6.13 Safety analysis 
Add the text in bold 
All subjects who receive at least dose one of study medication will be included in the analysis of 
safety. 
Safety measures will be summarized for the following subject cohorts for the open label phase: 
≠ All treated subjects; 
≠ Treated subjects without urinary evidence of illicit drug use (i.e. any positive result in 
the urine drug screen during the open-label phase, including all categories); and 
≠ Treated subjects with urinary evidence of illicit drug use (may be further subdivided by 
type of illicit drug used). 
Safety measures will only be summarized for all treated subjects for the double blind phase. 
 
Extent of exposure 
Extent of exposure will be described by whether the subject took the trial medication and the 
number of days exposure to double-blind study medication (last date of double-blind medication 
minus first date of double-blind medication + 1). Average daily dose of double-blind study 
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medication will also be calculated by number of doses/exposure (days). Exposure to open-label 
medication will also be calculated as last date of open-label medication – first date of open-label 
medication + 1. No allowance will be made for breaks in therapy in the exposure calculations. 
Average daily dose of open-label study medication will also be calculated.  If the date of last 
dosing is completely missing for the trial medication then the date of last dosing will be taken for 
analysis purposes as the date the medication was last dispensed.  As there are no open-label 
dosing dates recorded on the eCRF, dates of visits will be used instead. In particular it will 
be assumed that open-label dosing starts one day after double-blind dosing ceases. 
Justification 
 
To make the definitions clearer.  
 
Change 15 
Section 6.13 Safety analysis 
Vital Signs During the Double-Blind Phase 
The following text was amended: 
Vital signs (blood pressure and pulse [sitting or recumbent and standing], respiration, and 
temperature) will be measured at screening, baseline and before each dose and 3.5 hours after 
each dose (with the exception of the dose taken at 11 PM, where the measurement at 3.5 hours 
post-dose will not be done) during the double-blind phase. Summary statistics for observed and 
changes from screening will be tabulated at each follow-up for each vital sign parameter and at 
post-baseline double-blind endpoint for each variable.  
In addition the number and proportion of subjects having: 
≠ Systolic blood pressure ≥180mmHg and an increase of ≥ 20mmHg from baseline 
≠ Systolic blood pressure ≤ 90mmHg and a decrease ≥ 20mmHg from baseline 
≠ Diastolic blood pressure ≥ 105mmHg and an increase ≥ 15mmHg from baseline 
≠ Diastolic blood pressure ≤ 50mmHg and a decrease ≥ 15mmHg from baseline 
will be summarized at each follow-up visits.  
The text in bold was added to the following: 
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Vital signs (blood pressure and pulse [sitting or recumbent and standing], respiration, and 
temperature) will be measured at screening, baseline and before each dose and 3.5 hours after 
each dose (with the exception of the dose taken at 11 PM, where the measurement at 3.5 hours 
post-dose will not be done) during the double-blind phase. Summary statistics for observed and 
changes from screening will be tabulated at each follow-up for each vital sign parameter and at 
post-baseline double-blind endpoint for each variable.  
In addition the number and proportion of subjects having: 
≠ Systolic blood pressure ≥ 180 mmHg and an increase of  ≥ 20 mmHg from screening 
≠ Systolic blood pressure ≤ 90 mmHg and a decrease ≥ 20 mmHg from screening 
≠ Diastolic blood pressure ≥ 105 mmHg and an increase ≥ 15 mmHg from screening 
≠ Diastolic blood pressure ≤ 50 mmHg and a decrease ≥ 15 mmHg from screening 
will be summarized at each follow-up visits.  
 
REFERENCES 
Little, RJA and DB Rubin. Statistical analysis with missing data. Version 2. John Wiley & Sons; 
New York: 2002 
 
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Effective: 24-Dec-2014 
 
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PROPRIETARY AND CONFIDENTIAL 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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PROPRIETARY AND CONFIDENTIAL 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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PROPRIETARY AND CONFIDENTIAL 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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PROPRIETARY AND CONFIDENTIAL 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
 
Effective: 24-Dec-2014 
 
Page 28 of 29 
 
 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 1 
Version: Final 
Issue Date: 24-Dec-2014 
Effective: 24-Dec-2014 
 
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Approval for implementation of 
Statistical Analysis Plan Addendum 
Title: 
A Phase 3, Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Efficacy, Safety and Dose-Response 
Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable 
Dose Lofexidine Treatment (Days 8-14) 
 
Reference: 
USWM-LX1-3003-1/SAP Addendum/1 
 
 
 
 
Addendum No: 
1 
 
 
 
 
Date effective: 
24-Dec-2014 
 
 
 
 
Author: 
 Principal Statistician 
 
 
 
 
 reviewer: 
 Principal Statistician   
 
 
 
Author’s signature: 
 
 
Date: 
 
 
Reviewer’s signature: 
 
 Date: 
 
 
 
 
The above Statistical Analysis Plan Addendum has been reviewed and approved by the 
Sponsor: 
Name of Approver: 
 
  
 
Position: 
Medical Director, US WorldMeds, LLC 
 
  
 
Signature: 
 
 Date: 
 
 
 
  
 
Name of Approver: 
 
  
 
 
 
  
 
Position: 
Sr. Manager, Biometrics,  US WorldMeds, LLC  
  
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 1 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
ADDENDUM 2 
 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, 
Safety and Dose-Response Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine 
Treatment (Days 8-14) 
Protocol Ref: USWM-LX1-3003-1 
Date effective: 22-Jan-2015 
 
 
 
 
 
 
 
 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 2 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
SUMMARY OF SECTIONS 
 
1 
INTRODUCTION 
 
 
 
 
 
 
 
 
2 
CHANGES TO EXISTING ANALYSIS PLAN 
 
 
 
 
 
 
 
3 
TABLES TO BE INCLUDED IN THE CLINICAL STUDY REPORT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 3 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
1. INTRODUCTION 
 
This document is the second addendum to the statistical analysis plan for the analysis of the US 
WorldMeds, LLC study USWM-LX1-3003-1. The original statistical analysis plan was dated 18-
Jun-14 and amendment number 1 was dated 24-Dec-14. 
 
All decisions were taken prior to database lock. 
2. CHANGES TO EXISTING ANALYSIS PLAN 
Change 1 
 
Section 6.2 Derived Data 
 
Questionnaire Data 
The following sentence was revised in bold: 
 
In the event that component items used to calculate total scores for questionnaire data e.g. SOWS 
Gossop score are missing, then the total scores will be computed as the average of the non-
missing item scores multiplied by the total number of items (e.g. multiply by 10 for the 
SOWS-Gossop) comprising the total score.  This same method will be applied to all other 
questionnaire data to calculate total scores in a similar fashion.  
 
Justification 
 
To minimize the number of patients with missing total assessment scores due to missing single 
component items. This solution incorporates comments from the US Food and Drug 
Administration (FDA) in relation to the calculation of total scores based on non-missing item 
scores. 
 
Change 2 
Section 6.3 Analysis Populations 
The following sentence was added in bold: 
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Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 4 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
The Enrolled Population includes all subjects screened into the study irrespective of whether 
they received the study medication. 
Three principal analysis populations are defined as follows: 
 Intent-to-treat (ITT), consisting of all randomized subjects. Subjects will be assigned for 
analysis according to the group to which they are randomized. 
 Modified intent-to-treat (mITT), consisting of all subjects in the ITT group who received 
at least one dose of study medication. Subjects will be assigned for analysis according to 
the group to which they are randomized. 
 Safety consisting of all subjects who received at least one dose of study medication. 
Subjects will be assigned for analysis according to treatment received. 
 
Justification 
 
To further clarify the definition of the safety analysis population.  
 
Change 3 
  
Section 6.9.2 Sensitivity Analysis  
 
The following text will be added: 
 
Additionally, further efficacy analysis will be conducted using the area under the curve (AUC) 
from Days 1 through 7 of the SOWS-Gossop scores as the endpoint. The AUC will be calculated 
on the original scale of measurement based on the back-transformed log scale estimates from the 
pattern mixture analysis. The LS means of the daily SOWS-Gossop scores (Days 1 through 7) 
will be exponentiated to get the geometric mean SOWS-Gossop score for each day.  These back-
transformed scores will then be used to calculate the AUC using the trapezoidal rule. AUC 
summary statistics will be reported, no formal statistical analysis will be performed.   
 
Justification 
 
The additional analysis was added to incorporate comments from the US Food and Drug 
Administration (FDA) regarding an additional proposed efficacy analysis.  Since statistical 
inference on the AUCs, such as confidence intervals, would be difficult and the results at best 
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Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 5 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
approximate, due to the fact that a propagation of errors approach would be needed to 
accommodate the exponentiation of results from the log scale of measurement back to the 
original scale; we have elected to present the estimated AUC values as descriptive statistics. 
 
Change 4 
Section 6.10 Secondary Endpoint 
The following text was amended: 
The secondary efficacy endpoint is the completion status (i.e., whether a subject receives at least 
one dose of study medication on Day 7 and completes the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7). The proportion of subjects in each treatment arm who receive at least 
one dose of study medication on Day 7 and complete the 3.5-hour post-dose SOWS-Gossop 
assessment on Day 7 will be analyzed using a logistic regression model including fixed 
effects for treatment group and gender using the mITT population. One test will compare 
the 3.2 mg lofexidine group to placebo; a second will compare the 2.4 mg Lofexidine group to 
placebo. A sensitivity analysis will be performed on this endpoint using the ITT population. 
 
Justification 
 
Gender was inadvertently removed as a variable from the logistic regression model.  
 
 
Change 5 
 
 
Section 6.2 Assessments Recorded at Discontinuation Visit 
 
Add the following text related to handling assessments recorded on discontinuation visit: 
On days where a discontinuation visit is recorded on the same day as a scheduled visit, then the 
scheduled visit should be used be for analysis purposes and the discontinuation visit will be 
ignored.  If a discontinuation visit is recorded on a study day where no scheduled visit is 
recorded, then it should be assigned to the actual study day the visit was recorded. 
 
 
Justification 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 6 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
To further clarify a set of rules for how to handle assessments recorded on the date of 
discontinuation instead of the scheduled study visit.   
 
 
Change 6 
 
 
Section 6.9.1 Principal Analysis  
 
The following text in bold has been revised: 
A pattern-mixture approach5 will be used in assessing SOWS-Gossop from Days 1 to 7 inclusive 
using the mITT population. 
  
It will be assumed that subjects randomized to lofexidine who withdraw from the study will have 
a time trajectory comparable to placebo post withdrawal. The pattern-mixture model will be 
implemented using multiple imputations (Ratitch6, 2011). The imputation of missing values and 
the analysis will be performed multiple times (20 imputed datasets) with the initial seed value set 
at ‘123’, and the inference of this sensitivity analysis will be based on the combined estimates 
using the standard multiple imputation technique. This method is detailed in the section entitled 
“Pattern-Mixture Model with Control-Based Pattern Imputation” (Ratitch7, 2013).  Briefly, the 
initial step is to impute the relatively rare, non-monotone missing data via the MCMC Option of 
SAS® PROC MI. The imputation model will include as predictors an indicator variable for 
gender (1 d.f.), two indicator variables for treatment (2 d.f), the Baseline value, and 
variables for Day 1 through Day 7 data. This step uses iterative methods, with which non-
convergence is a possibility; should an MCMC imputation step not converge, alternative 
models will be developed by dropping time point variables from the model, one at a time 
starting at Day 7, until convergence is achieved. For example, if non-convergence occurs 
for the model that includes all the time point variables from baseline through Day 7, the 
next model to be considered will have all time point variables from baseline through Day 6, 
as well as the indicators for treatment and gender. The next model, if needed, would have 
all time point variables from baseline through Day 5, and so forth. Should this approach 
not succeed, ad hoc methods to impute non-monotone missing data will be developed and 
documented.  
These contingency models for non-convergence, as well as the modeling of data with a 
monotone missing pattern, will require additional random number seeds. As stated in the 
SAP, the seed for the first step of the monotone missing imputation is ‘234’. The following 
additional seeds are to be used in the order shown for any additional modeling of non-
monotone missing data as well as for the subsequent imputation of monotone missing data. 
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Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 7 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
1. 345 
2. 456 
3. 567 
4. 678 
5. 789 
6. 890 
7. 901 
8. 012 
9. 124 
10. 245 
11. 356 
12. 467 
13. 578 
14. 689 
15. 790 
16. 145 
17. 256 
18. 367 
19. 478 
20. 589 
 
 
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Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 8 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
Justification 
 
To acknowledge the possibility of non-convergence and to clarify a process to implement 
systematic adjustments to the model to achieve convergence.  To simplify the imputation model 
by modeling the entire data set once rather than for each separate combination of treatment and 
gender. To pre-specify a list of random number seeds for use in the imputation process. 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 9 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 10 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
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Protocol Number USWM-LX1-3003-1 
Statistical Analysis Plan Addendum 2 
Version: Final 
Issue Date: 22-Jan-2015
Effective: 22-Jan-2015 
 
Page 11 of 11 
 
 
 
 
 
PROPRIETARY AND CONFIDENTIAL 
 
Approval for implementation of 
Statistical Analysis Plan Addendum 
Title: 
A Phase 3, Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, Efficacy, Safety and Dose-Response 
Study of Lofexidine in the Treatment of Opioid 
Withdrawal (Days 1-7) Followed by Open-Label, Variable 
Dose Lofexidine Treatment (Days 8-14) 
 
Reference: 
USWM-LX1-3003-1/SAP Addendum/1 
 
 
 
 
Addendum No: 
2 
 
 
 
 
Date effective: 
22-Jan-2015 
 
 
 
 
Author: 
 Principal Statistician 
 
 
 
 
 reviewer: 
 Principal Statistician   
 
 
 
Author’s signature: 
 
 
Date: 
 
 
Reviewer’s signature: 
 
 Date: 
 
 
 
 
The above Statistical Analysis Plan Addendum has been reviewed and approved by the 
Sponsor: 
Name of Approver: 
 
  
 
Position: 
Medical Director, US WorldMeds, LLC 
 
  
 
Signature: 
 
 Date: 
 
 
 
  
 
Name of Approver: 
 
  
 
 
 
  
 
Position: 
Sr. Manager, Biometrics,  US WorldMeds, LLC  
  
 
Signature: 
 
 Date: 
 
 
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