Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Efficacy, Safety, and Dose-Response Study of Lofexidine for Treatment of Opioid Withdrawal (Days 1-7) Followed by Open-Label, Variable Dose Lofexidine Treatment (Days 8-14)
Phase: PHASE3
Conditions: Opioid Dependence, Acute Opioid Withdrawal Syndrome
Sponsor: USWM, LLC (dba US WorldMeds)

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 
 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 1

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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 2

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.”
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 3

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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 4

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 5

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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 6

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 6 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 7

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 7 of 80
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);
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 8

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 8 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 9

Protocol No. USWM-LXl-3003-1, Amendment No. 02 
May 6, 2013 
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 10

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 10 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 11

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 11 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 12

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 12 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 13

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 13 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 14

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 14 of 80
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);
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 15

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 15 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 16

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 16 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 17

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 17 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 18

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 18 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 19

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 19 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 20

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 20 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 21

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 21 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 22

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 22 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 23

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 23 of 80
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 24

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 24 of 80
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 25

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 25 of 80
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 26

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 26 of 80
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 27

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 27 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 28

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 28 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 29

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 29 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 30

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 30 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 31

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 31 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 32

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 32 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 33

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 33 of 80
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.”
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 34

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 34 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 35

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 35 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 36

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 36 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 37

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 37 of 80
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. 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 38

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 38 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 39

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 39 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 40

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 40 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 41

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 41 of 80
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 (
).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 42

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 42 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 43

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 43 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 44

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 44 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 45

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 45 of 80
15 CLINICAL EVALUATIONS
A detailed Schedule of Assessments to be done in the study is provided in Table 1.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 46

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 46 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 47

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 47 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 48

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 48 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 49

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 49 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 50

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 50 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 51

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 51 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 52

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 52 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 53

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 53 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 54

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 54 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 55

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 55 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 56

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 56 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 57

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 57 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 58

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 58 of 80
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;
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 59

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 59 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 60

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 60 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 61

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 61 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 62

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 62 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 63

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 63 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 64

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 64 of 80
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 65

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 65 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 66

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 66 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 67

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 67 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 68

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 68 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 69

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 69 of 80
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 70

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 70 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 71

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 71 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 72

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 72 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 73

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 73 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 74

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 74 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 75

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 75 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 76

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 76 of 80
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, 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 77

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 77 of 80
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 78

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 78 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 79

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 79 of 80
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 80

Protocol No. USWM-LX1-3003-1, Amendment No. 02
May 6, 2013
Confidential Information
Page 80 of 80
21.
Little RJA.  Pattern-mixture models for multivariate incomplete data.  Journal of the
American Statistical Association 1993;88:125-134.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 81

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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 102

Confidential Information
Page 1 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 103

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 2 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 104

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 3 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 105

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 4 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 106

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 5 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 107

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 6 of 73
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):
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 108

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 7 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 109

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 8 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 110

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 9 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 111

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 10 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 112

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 11 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 113

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 12 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 114

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 13 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 115

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 14 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 116

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 15 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 117

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 16 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 118

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 17 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 119

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 18 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 120

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 19 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 121

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 20 of 73
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 122

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 21 of 73
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 123

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 22 of 73
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 124

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 23 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 125

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 24 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 126

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 25 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 127

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 26 of 73
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;
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 128

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 27 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 129

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 28 of 73
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:
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 130

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 29 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 131

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 30 of 73
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,
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 132

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 31 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 133

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 32 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 134

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 33 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 135

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 34 of 73
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. 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 136

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 35 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 137

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 36 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 138

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 37 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 139

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 38 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 140

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 39 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 141

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 40 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 142

Protocol No. USWM-LX1-3003-1, Amendment No. 01
March 8, 2013
Confidential Information
Page 41 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 143

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 42 of 73
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
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 144

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 43 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 145

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 44 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 146

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 45 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 147

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 46 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 148

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 47 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 149

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 48 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 150

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 49 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 151

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 50 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 152

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 51 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 153

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 52 of 73
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;
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 154

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 53 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 155

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 54 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 156

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 55 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 157

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 56 of 73
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).
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 158

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 57 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 159

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 58 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 160

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 59 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 161

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 60 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 162

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 61 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 163

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 62 of 73
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;
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 164

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 63 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 165

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 64 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 166

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 65 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 167

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 66 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 168

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 67 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 169

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 68 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 170

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 69 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 171

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 70 of 73
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 
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 172

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 71 of 73
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 173

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 72 of 73
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.
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.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 174

Protocol No. USWM-LX1-3003-1, Amendment No. 1
March 8, 2013
Confidential Information
Page 73 of 73
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.
21.
Little RJA.  Pattern-mixture models for multivariate incomplete data.  Journal of the
American Statistical Association 1993;88:125-134.
209229
uswm-lx1-3003-1-protocol-and-amendments
 Pg. 175