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.