Main Study of Lofexidine and Methadone Pharmacodynamic Interaction in Methadone Maintained Patients

NCT01650649 | Completed Phase 1

• 2 other identifiers: USWM-LX1-1005-21U01DA030916-01
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this study is to assess QTc (an interval of the heart rhythm) interaction effects between lofexidine and methadone. The secondary objectives of the study are to evaluate the safety and tolerability of lofexidine by evaluating and monitoring pharmacokinetics (amounts of drug in the blood), vital signs (heart rate and blood pressure) and adverse events (side effects) when co-administered with methadone; to describe effects on opiate withdrawal when lofexidine is introduced following a 50% methadone dose reduction, as required to elicit a withdrawal response; and to evaluate the QTc interaction effects of lofexidine compared with placebo. The investigators hypothesize that while both agents (lofexidine and methadone) are known to prolong the QTc interval, the combination of the drugs will not create an additive effect which creates a significant safety concern. The investigators further hypothesize that subjects will be able to tolerate the therapeutic dose of lofexidine (0.8 mg four times daily) when the methadone maintenance dose is lowered to elicit withdrawal.

Conditions

Opioid Dependence; Methadone Withdrawal Syndrome

Keywords

lofexidine; methadone; interaction; pharmacodynamic; ECG; QTc

Outcome Measures

Primary Outcomes (1)

• Changes in QTc Interval

  The ECG analysis will be conducted by a central laboratory under blinded review. QTc intervals at baseline (methadone maintenance dose only) will be compared to a time matched profile at each increasing lofexidine dose (as tolerated by the subjects), both before and after a withdrawal response is elicited.

  baseline and at each escalating lofexidine dosing plateau day 3 (participant time in the study will vary based on tolerability but each dose plateau will be evaluated after 3 days at any given dose level)

Secondary Outcomes (6)

• Change from Baseline in the Short Opioid Withdrawal Scale (SOWS)

  baseline and daily assessments during methadone withdrawal phases (participant time in withdrawal will vary based on lofexidine tolerability, however on average subjects will be in a methadone withdrawal phase of the study for approximately 10 days)

• Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS)

  baseline and daily assessments during methadone withdrawal phases (participant time in withdrawal will vary based on lofexidine tolerability, however on average subjects will be in a methadone withdrawal phase of the study for approximately 10 days)

• Methadone Area Under the Curve (AUC)

  Baseline pre-dose, 2, 3, 4, 5, 6, 10 and 24 hours; plateau days pre-dose, 0.5, 1 , 2, 3, 4, and 5 hours post dose

• Lofexidine Area Under the Curve (AUC)

  plateau days pre-dose, 0.5, 1 , 2, 3, 4, and 5 hours post dose

• Change in Vital Signs

  baseline & 15 min prior to each dose & 3.5 hr after 8 AM, 1 and 6 PM doses on each day lofexidine dose is escalated [time in study will vary, but participants will be exposed to up 3 different lofexidine doses (from 0.4 QID to 0.8 mg QID)]

Study Arms (2)

Lofexidine Titration in Methadone Maintained Subjects

ACTIVE COMPARATOR

Methadone maintained subjects will be titrated on lofexidine up to the target therapeutic dose of 0.8 mg QID (4 tablets QID) or to the highest level tolerated. Following this initial titration attempt, all subjects will have their methadone dose reduced by 50% and lofexidine titration efforts will resume.

Drug: Lofexidine HCl

Placebo titration in methadone maintained subjects

PLACEBO COMPARATOR

Methadone maintained subjects will be titrated on placebo tablets in ascending doses of 1 tablet starting with 2 tablets (e.g. Day 1 2 tablets QID, Day 2 3 tablets QID, etc) to mimic titration for subjects randomized to lofexidine.

Drug: Lofexidine-matching sugar pill

Interventions

Lofexidine HCl DRUG

Lofexidine HCl 0.2 mg tablets titrated in ascending doses of 0.2 mg (1 tablet) QID starting at 0.4 mg (2 tablets) QID \[e.g. Day 1 0.4 mg (2 tablets) QID, Day 2 0.6 (3 tablets)QID, etc\] as described in the treatment arm. Option to down-titrate to 0.2 mg (1 tablet) QID if 0.4 mg (2 tablets) QID dose not initially tolerated.

Lofexidine Titration in Methadone Maintained Subjects

Lofexidine-matching sugar pill DRUG

Lofexidine-matching sugar pill tablets titrated in ascending doses of 1 tablet starting at 2 tablets QID (e.g. Day 1 2 tablets QID, Day 2 3 tablets QID, etc)as described in the treatment arm. Option to down-titrate to 1 tablet QID if 2 tablets not initially tolerated.

Placebo titration in methadone maintained subjects

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adult male and/or female, 18 to 60 years of age (inclusive).
• Receiving methadone maintenance treatment for opioid dependence at a stable once-daily dose of 80-120 mg for at least 4 weeks prior to check-in for the Inpatient Treatment Visit.
• Body mass index ≥ 18 and ≤ 35 (kg/m2).
• Normal screening results or abnormal results that have been deemed by the Investigator as clinically insignificant.
• Able to understand and willing to sign an informed consent form (ICF).
• Females practicing adequate birth control or non-childbearing potential. Medically acceptable birth control methods for this study include intrauterine device (IUD); vasectomized partner (minimum of 6 months); post-menopausal (at least 2 years); surgically sterile (at least 6 months); double barrier (diaphragm with spermicide, condoms with vaginal spermicide); abstinence; implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive months prior to study dosing and throughout the study duration; and oral, patch and injected hormonal contraceptives or vaginal hormonal device (ie, NuvaRing®) in use for at least 3 consecutive months prior to study dosing and throughout the study duration.

You may not qualify if:

• Abnormal cardiovascular exam at screening and before randomization, including any of the following:
• clinically significant abnormal electrocardiogram (ECG) (eg, significant first degree atrioventricular block, complete left bundle branch block \[LBBB\], second or third degree heart block, clinically significant arrhythmia, or QTc interval (machine read) greater than 450 msec for males and greater than 470 msec for females)\*
• heart rate \< 55 bpm or symptomatic bradycardia\*
• systolic blood pressure (SBP) \< 95 mmHg or symptomatic hypotension\*
• diastolic blood pressure (DBP) \< 65 mmHg\*
• blood pressure (BP) \> 155/95 mmHg\*
• change in orthostatic SBP, DBP, or heart rate \>25% below sitting values
• prior history of myocardial infarction (MI) or evidence of prior MI on ECG\*
• history of long QT syndrome or relative with this condition
• history of syncopal episodes
• intraventricular conduction delay with QRS duration \>120 ms
• evidence of ventricular pre-excitation (eg, Wolff Parkinson White syndrome) \*ECGs and vitals may be repeated as appropriate in order to confirm values and rule out extraneous results.
• History or presence of significant or clinically unstable cardiovascular (including atrial fibrillation, congestive heart failure, myocardial ischemia, indwelling pacemaker), hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, psychiatric, neurologic, or dermatologic disease.
• History or presence of any degree of chronic obstructive pulmonary disease.
• History of suicidal ideations or depression requiring professional intervention including counseling or antidepressant medication over the past 12 months.

Sponsors & Collaborators

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

Study Sites (1)

Lifetree Clinical Research

Salt Lake City, Utah, 84106, United States

Location

MeSH Terms

Conditions

Opioid-Related Disorders

Interventions

lofexidine

Condition Hierarchy (Ancestors)

Narcotic-Related Disorders; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Study Officials

• Charles W. Gorodetzky, MD, PhD

  US WorldMeds

  STUDY DIRECTOR

• James A Longstreth, PhD

  US WorldMeds

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2012
• First Posted: July 26, 2012
• Study Start: July 1, 2012
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: October 26, 2017

Record last verified: 2017-10

Locations

US (1)