Efficacy, Safety and Dose-Response Study Followed by Open-Label Study of Lofexidine Treatment of Opioid Withdrawal

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

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

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

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

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

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

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

Inclusion Criteria:

- Male or female at least 18 years of age.

- Currently 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).

- Seeking treatment for opioid dependence.

- Score of ≥2 on the Objective Opiate Withdrawal Scale (OOWS-Handelsman) at Baseline.

- 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.

- Urine toxicology screen positive for opioids but negative for methadone and
buprenorphine.

- Females of childbearing potential must agree to using birth control methods and must
have had documented proof.

- 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:

- Female subject who is pregnant or lactating.

- Self-reported use of methadone or buprenorphine in the past 14 days.

- Serious medical illnesses including, but not limited to: seizures, pancreatic disease,
liver disease, exposure to a hepatitis virus, and positive hepatitis results.

- 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.

- 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.

- Abnormal cardiovascular exam at screening and before randomization, including any of
the following: 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); heart rate less than 55 bpm
or symptomatic bradycardia; systolic blood pressure (SBP) less than 95 mmHg or
symptomatic hypotension; diastolic blood pressure (DBP) less than 65 mmHg; blood
pressure (BP) greater than 155/95 mmHg; and prior history of myocardial infarction.

- Clinically significant abnormal laboratory values.

- 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.

- Currently dependent (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.

- Donated blood within the last 8 weeks.

- Participated in an investigational drug study within the past 3 months.

- Has "poor" veins that even a single venipuncture cannot be obtained during screening.

- Active tuberculosis (positive tuberculin test and/or confirmatory diagnostic chest
x-ray).

- Active syphilis.