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

• Sponsor: USWM, LLC (dba US WorldMeds) (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01863186
• Collaborator: National Institute on Drug Abuse (NIDA) (NIH)
• Enrollment: 603
• Locations: 18
• Arms: 4
• Duration (Months): 18
• Patients Per Site: 33.5
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Opioid Dependence; Acute Opioid Withdrawal Syndrome	Drug: Lofexidine HCl; Drug: Placebo; Drug: Open Label Lofexidine HCL	Phase 3

Detailed Description

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

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

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

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

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

A subject will be discontinued from the study if any of the following criteria are met:

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

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 603 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: Jun 1, 2013
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lofexidine HCl (2.4mg dose) 225 subjects will be randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.	Drug: Lofexidine HCl; Lofexidine HCl tablets will be available in 0.2 mg tablets. Lofexidine will be provided in total daily doses as indicated during the double blind portion of the study.; Drug: Placebo; Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.
Active Comparator: Lofexidine HCl (3.2mg dose) 225 subjects will be randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.	Drug: Lofexidine HCl; Lofexidine HCl tablets will be available in 0.2 mg tablets. Lofexidine will be provided in total daily doses as indicated during the double blind portion of the study.
Placebo Comparator: Placebo 150 subjects will be randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days.	Drug: Placebo; Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.
Other: Open Label Lofexidine HCl During the open-label portion of the study, subjects will be given the option to receive lofexidine HCl tablets for up to 7 days. Dosing regimens are at the discretion of the Investigator.	Drug: Open Label Lofexidine HCL; Lofexidine HCl tablets will are available in 0.2 mg tablets. During the optional open-label portion of the study, Lofexidine HCl can be prescribed at the discretion of the Investigator but total daily dose will not exceed 3.2 mg.

Outcome Measures

Primary Outcome Measures

1. Difference Between the Overall Means From Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) Scores [Days 1 through 7]

   The SOWS-Gossop was completed by the mITT population subject at baseline, once daily at 3.5 hours after the first dose of the study medication on Days 1 to 7. It consists of 10 items that are scored on a 4-point scale; 0=none, 1=mild, 2=moderate, and 3=severe. The overall score is the simple sum of the 10-item scores (minimum overall score of 0, maximum score of 30). Higher individual scores on the scale indicate greater symptom severity. However, as the outcome measure is a difference from placebo, a lower number indicates a better outcome. mITT population: all randomized subjects who received at least 1 dose of study medication

Secondary Outcome Measures

1. Completion Status [Day 7]

   The percentage 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Clovis	California	United States	93611
2		Escondido	California	United States	92025
3		San Diego	California	United States
4		Miami	Florida	United States	33136
5		Orlando	Florida	United States	32806
6		Atlanta	Georgia	United States	30308
7		Oak Park	Illinois	United States	60301
8		Lake Charles	Louisiana	United States	70629
9		Baltimore	Maryland	United States	21229
10		Flowood	Mississippi	United States
11		Saint Louis	Missouri	United States
12		Dayton	Ohio	United States
13		Mason	Ohio	United States	45050
14		Austin	Texas	United States	78731
15		Dallas	Texas	United States	75208
16		DeSoto	Texas	United States	75115
17		Orem	Utah	United States	84058
18		Salt Lake City	Utah	United States	84106

Sponsors and Collaborators

• USWM, LLC (dba US WorldMeds)
• National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Charles W Gorodetzky, MD, PhD, US WorldMeds

Study Documents (Full-Text)

• Study Protocol - May 6, 2013
• Statistical Analysis Plan - Jan 22, 2015
• Informed Consent Form - Jun 25, 2013

More Information

Publications

None provided.

• Responsible Party: USWM, LLC (dba US WorldMeds)
• ClinicalTrials.gov Identifier: NCT01863186
• Other Study ID Numbers: USWM-LX1-3003-1; 1U01DA033276-01A1
• First Posted: May 27, 2013
• Last Update Posted: Mar 22, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by USWM, LLC (dba US WorldMeds): lofexidine; opioid dependence; acute withdrawal syndrome; opioid withdrawal
• Additional relevant MeSH terms: Opioid-Related Disorders; Substance Withdrawal Syndrome; Lofexidine; Clonidine

Study Results

Participant Flow

Arm/Group Title	DB: Lofexidine HCl 2.4mg Dose	DB: Lofexidine HCl 3.2mg Dose	DB: Placebo	OL: All Lofexidine HCl
Arm/Group Description	Participants were randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.	Participants were randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.	Participants were randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. Placebo: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.	Participants were given the option to receive lofexidine HCl tablets for up to 7 additional days, following the double blind period. Dosing regimens are at the discretion of the Investigator, but total daily dose will not exceed 3.2 mg.
Period Title: Double-blind Phase
STARTED	229	222	151	0
COMPLETED	95	88	42	0
NOT COMPLETED	134	134	109	0
Period Title: Double-blind Phase
STARTED	0	0	0	83
COMPLETED	0	0	0	70
NOT COMPLETED	0	0	0	13

Baseline Characteristics

Arm/Group Title	DB: Lofexidine HCl 2.4mg Dose	DB: Lofexidine HCl 3.2mg Dose	DB: Placebo	Total
Arm/Group Description	Participants were randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.	Participants were randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.	Participants were randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. Placebo: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.	Total of all reporting groups
Overall Participants	229	222	151	602
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	35 (10.8)	35 (10.5)	36 (11.9)	35 (11.0)
Sex: Female, Male (Count of Participants)
Female	67 29.3%	64 28.8%	44 29.1%	175 29.1%
Male	162 70.7%	158 71.2%	107 70.9%	427 70.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	33 14.4%	28 12.6%	22 14.6%	83 13.8%
Not Hispanic or Latino	196 85.6%	194 87.4%	129 85.4%	519 86.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	2 0.9%	2 1.3%	4 0.7%
Asian	1 0.4%	3 1.4%	1 0.7%	5 0.8%
Native Hawaiian or Other Pacific Islander	0 0%	2 0.9%	3 2%	5 0.8%
Black or African American	54 23.6%	48 21.6%	26 17.2%	128 21.3%
White	169 73.8%	158 71.2%	117 77.5%	444 73.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	5 2.2%	9 4.1%	2 1.3%	16 2.7%
Body weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	76.0 (16.88)	76.1 (16.59)	76.0 (14.94)	76.1 (16.29)
BMI (kg/m^2) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.1 (4.71)	25.1 (5.32)	25.1 (4.63)	25.1 (4.92)

Outcome Measures

1. Primary Outcome

Title	Difference Between the Overall Means From Short Opiate Withdrawal Scale of Gossop (SOWS-Gossop) Scores
Description	The SOWS-Gossop was completed by the mITT population subject at baseline, once daily at 3.5 hours after the first dose of the study medication on Days 1 to 7. It consists of 10 items that are scored on a 4-point scale; 0=none, 1=mild, 2=moderate, and 3=severe. The overall score is the simple sum of the 10-item scores (minimum overall score of 0, maximum score of 30). Higher individual scores on the scale indicate greater symptom severity. However, as the outcome measure is a difference from placebo, a lower number indicates a better outcome. mITT population: all randomized subjects who received at least 1 dose of study medication
Time Frame	Days 1 through 7

Outcome Measure Data

Analysis Population Description

mITT population Participants Analyzed does not match the Participant Flow because of missing data.

Arm/Group Title	DB: Lofexidine HCl 2.4mg Dose	DB: Lofexidine HCl 3.2mg Dose	DB: Placebo
Arm/Group Description	Participants were randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.	Participants were randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.	Participants were randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. Placebo: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.
Measure Participants	229	222	151
Day 1	7.8 (6.00)	7.6 (6.75)	9.4 (6.81)
Day 2	10.2 (6.83)	9.9 (7.38)	13.9 (8.29)
Day 3	7.6 (5.53)	7.4 (6.34)	10.9 (6.76)
Day 4	5.7 (5.32)	5.5 (5.36)	9.2 (6.81)
Day 5	4.7 (4.60)	4.5 (4.96)	6.4 (5.91)
Day 6	3.6 (3.97)	3.2 (4.10)	4.4 (5.80)
Day 7	2.7 (3.45)	2.3 (3.23)	2.7 (4.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB: Lofexidine HCl 2.4mg Dose, DB: Placebo
	Comments	Due to the amount of missing data a pattern mixture model (or Jump to Reference) was utilized. The SOWS-Gossop total scores were log transformed. Each subjects available data Days 1-7 were included. The datasets created by the pattern mixture model were analyzed using a Mixed Model Repeated Measures model that included fixed effects for treatment group, baseline, sex, study day (1-7), and treatment group-by-day interaction. The overall estimate for each treatment group were compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0166
	Comments
	Method	Pattern Mixture Model
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB: Lofexidine HCl 3.2mg Dose, DB: Placebo
	Comments	Due to the amount of missing data a pattern mixture model (or Jump to Reference) was utilized. The SOWS-Gossop total scores were log transformed. Each subjects available data Days 1-7 were included. The datasets created by the pattern mixture model were analyzed using a Mixed Model Repeated Measures model that included fixed effects for treatment group, baseline, sex, study day (1-7), and treatment group-by-day interaction. The overall estimate for each treatment group were compared.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0033
	Comments
	Method	Pattern Mixture Model
	Comments

2. Secondary Outcome

Title	Completion Status
Description	The percentage 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.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

The percentage of subjects in each treatment arm who complete the double-blind phase of the study (defined as those 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).

Arm/Group Title	DB: Lofexidine HCl 2.4mg Dose	DB: Lofexidine HCl 3.2mg Dose	DB: Placebo
Arm/Group Description	Participants were randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.	Participants were randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.	Participants were randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. Placebo: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.
Measure Participants	229	222	151
Yes/Complete	95 41.5%	88 39.6%	42 27.8%
No/Did Not Complete	134 58.5%	134 60.4%	109 72.2%

Adverse Events

Time Frame	Through study completion (14 Days)
Arm/Group Title	DB: Lofexidine HCl 2.4mg Dose		DB: Lofexidine HCl 3.2mg Dose		DB: Placebo		OL: All Lofexidine HCl
Arm/Group Description	Participants were randomized to receive 2.4 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 2.4 mg (one tablet in each dose will be a placebo tablet to maintain the blind) for up to 7 days.		Participants were randomized to receive 3.2 mg total daily dose of lofexidine HCl during the double-blind period of the study. Subjects will take 4 tablets QID for a total daily dose of 3.2 mg for up to 7 days.		Participants were randomized to receive placebo during the double-blind period of the study. Subjects will take 4 tablets QID for up to 7 days. Placebo: Lofexidine-matching tablets without the active pharmaceutical ingredient will be provided as 4 tablets QID during the double-blind portion of the study to subjects randomized to placebo.		Participants were given the option to receive lofexidine HCl tablets for up to 7 additional days, following the double blind period. Dosing regimens are at the discretion of the Investigator, but total daily dose will not exceed 3.2 mg.
All Cause Mortality
	DB: Lofexidine HCl 2.4mg Dose		DB: Lofexidine HCl 3.2mg Dose		DB: Placebo		OL: All Lofexidine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/229 (0%)		1/222 (0.5%)		0/151 (0%)		0/83 (0%)
Serious Adverse Events
	DB: Lofexidine HCl 2.4mg Dose		DB: Lofexidine HCl 3.2mg Dose		DB: Placebo		OL: All Lofexidine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/229 (0%)		5/222 (2.3%)		2/151 (1.3%)		0/83 (0%)
Infections and infestations
Acute hepatitis C	0/229 (0%)		0/222 (0%)		1/151 (0.7%)		0/83 (0%)
Injury, poisoning and procedural complications
Overdose	0/229 (0%)		1/222 (0.5%)		0/151 (0%)		0/83 (0%)
Toxicity to various agents	0/229 (0%)		1/222 (0.5%)		0/151 (0%)		0/83 (0%)
Investigations
Electrocardiogram QT prolonged	0/229 (0%)		0/222 (0%)		1/151 (0.7%)		0/83 (0%)
Nervous system disorders
Syncope	0/229 (0%)		2/222 (0.9%)		0/151 (0%)		0/83 (0%)
Psychiatric disorders
Suicidal ideation	0/229 (0%)		1/222 (0.5%)		0/151 (0%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	DB: Lofexidine HCl 2.4mg Dose		DB: Lofexidine HCl 3.2mg Dose		DB: Placebo		OL: All Lofexidine HCl
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	216/229 (94.3%)		211/222 (95%)		134/151 (88.7%)		46/83 (55.4%)
Cardiac disorders
Bradycardia	54/229 (23.6%)		70/222 (31.5%)		8/151 (5.3%)		3/83 (3.6%)
Tachycardia	6/229 (2.6%)		2/222 (0.9%)		13/151 (8.6%)		5/83 (6%)
Gastrointestinal disorders
Abdominal pain	9/229 (3.9%)		5/222 (2.3%)		9/151 (6%)		0/83 (0%)
Abdominal pain upper	19/229 (8.3%)		18/222 (8.1%)		12/151 (7.9%)		4/83 (4.8%)
Diarrhoea	51/229 (22.3%)		48/222 (21.6%)		35/151 (23.2%)		5/83 (6%)
Dry mouth	22/229 (9.6%)		24/222 (10.8%)		2/151 (1.3%)		4/83 (4.8%)
Constipation	14/229 (6.1%)		17/222 (7.7%)		4/151 (2.6%)		2/83 (2.4%)
Nausea	50/229 (21.8%)		27/222 (12.2%)		32/151 (21.2%)		0/83 (0%)
Vomiting	23/229 (10%)		19/222 (8.6%)		24/151 (15.9%)		1/83 (1.2%)
General disorders
Pain	51/229 (22.3%)		42/222 (18.9%)		36/151 (23.8%)		4/83 (4.8%)
Drug withdrawal syndrome	14/229 (6.1%)		14/222 (6.3%)		7/151 (4.6%)		0/83 (0%)
Fatigue	14/229 (6.1%)		16/222 (7.2%)		6/151 (4%)		3/83 (3.6%)
Musculoskeletal and connective tissue disorders
Back pain	9/229 (3.9%)		9/222 (4.1%)		9/151 (6%)		2/83 (2.4%)
Myalgia	30/229 (13.1%)		22/222 (9.9%)		25/151 (16.6%)		1/83 (1.2%)
Nervous system disorders
Headache	30/229 (13.1%)		31/222 (14%)		23/151 (15.2%)		4/83 (4.8%)
Sedation	29/229 (12.7%)		27/222 (12.2%)		8/151 (5.3%)		1/83 (1.2%)
Dizziness	44/229 (19.2%)		51/222 (23%)		4/151 (2.6%)		3/83 (3.6%)
Somnolence	25/229 (10.9%)		29/222 (13.1%)		8/151 (5.3%)		0/83 (0%)
Psychiatric disorders
Anxiety	10/229 (4.4%)		10/222 (4.5%)		10/151 (6.6%)		5/83 (6%)
Insomnia	117/229 (51.1%)		123/222 (55.4%)		73/151 (48.3%)		4/83 (4.8%)
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea	8/229 (3.5%)		6/222 (2.7%)		9/151 (6%)		1/83 (1.2%)
Cough	13/229 (5.7%)		8/222 (3.6%)		4/151 (2.6%)		0/83 (0%)
Vascular disorders
Hypertension	3/229 (1.3%)		7/222 (3.2%)		15/151 (9.9%)		1/83 (1.2%)
Hypotension	69/229 (30.1%)		67/222 (30.2%)		2/151 (1.3%)		7/83 (8.4%)
Orthostatic hypotension	67/229 (29.3%)		94/222 (42.3%)		7/151 (4.6%)		4/83 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.