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

NCT ID: NCT01863186

Last Updated: 2022-03-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 603 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-06-30
• Study Completion Date: 2014-12-31

Brief Summary

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

Detailed Description

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

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

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

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

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

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

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

Conditions

Opioid Dependence; Acute Opioid Withdrawal Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Lofexidine HCl

Intervention Type: DRUG

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

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Lofexidine HCl

Intervention Type: DRUG

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

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

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.

Group Type: OTHER

Open Label Lofexidine HCL

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

USWM, LLC (dba US WorldMeds)

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Charles W Gorodetzky, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

US WorldMeds

Locations

Clovis, California, United States

Escondido, California, United States

San Diego, California, United States

Miami, Florida, United States

Orlando, Florida, United States

Atlanta, Georgia, United States

Oak Park, Illinois, United States

Lake Charles, Louisiana, United States

Baltimore, Maryland, United States

Flowood, Mississippi, United States

St Louis, Missouri, United States

Dayton, Ohio, United States

Mason, Ohio, United States

Austin, Texas, United States

Dallas, Texas, United States

DeSoto, Texas, United States

Orem, Utah, United States

Salt Lake City, Utah, United States

Countries

United States

References

Alam D, Tirado C, Pirner M, Clinch T. Efficacy of lofexidine for mitigating opioid withdrawal symptoms: results from two randomized, placebo-controlled trials. J Drug Assess. 2020 Jan 8;9(1):13-19. doi: 10.1080/21556660.2019.1704416. eCollection 2020.

Reference Type: DERIVED

PMID: 32002194 (View on PubMed)

Darpo B, Pirner M, Longstreth J, Ferber G. Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal. Drug Alcohol Depend. 2019 Dec 1;205:107596. doi: 10.1016/j.drugalcdep.2019.107596. Epub 2019 Sep 27.

Reference Type: DERIVED

PMID: 31606589 (View on PubMed)

Fishman M, Tirado C, Alam D, Gullo K, Clinch T, Gorodetzky CW; CLEEN-SLATE Team. Safety and Efficacy of Lofexidine for Medically Managed Opioid Withdrawal: A Randomized Controlled Clinical Trial. J Addict Med. 2019 May/Jun;13(3):169-176. doi: 10.1097/ADM.0000000000000474.

Reference Type: DERIVED

PMID: 30531234 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1U01DA033276-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

USWM-LX1-3003-1

Identifier Type: -

Identifier Source: org_study_id