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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
US WorldMeds LLC
ClinicalTrials.gov Identifier:
NCT01650649
First received: July 9, 2012
Last updated: January 15, 2013
Last verified: January 2013
  Purpose

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.


Condition Intervention Phase
Opioid Dependence
Methadone Withdrawal Syndrome
Drug: Lofexidine HCl
Drug: Lofexidine-matching sugar pill
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Electrocardiographic Effects of Lofexidine When Administered Orally to Methadone Maintained Adult Subjects

Resource links provided by NLM:


Further study details as provided by US WorldMeds LLC:

Primary Outcome Measures:
  • Changes in QTc Interval [ Time Frame: 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) ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Change from Baseline in the Short Opioid Withdrawal Scale (SOWS) [ Time Frame: baseline and daily assessments during methadone withdrawal phases (participant time in withdrawal will vary based on lofexdine tolerability, however on average subjects will be in a methadone withdrawal phase of the study for approximately 10 days) ] [ Designated as safety issue: No ]
    SOWS Scores at Baseline (representing when a patient is on his/her normal methadone maintenance dose when withdrawal should be minimal or zero) will be compared to SOWS Scores during methadone reduction phases of the study to determine how the intervention is affecting withdrawal. Smaller changes from baseline indicate better control of withdrawal symptoms.

  • Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) [ Time Frame: baseline and daily assessments during methadone withdrawal phases (participant time in withdrawal will vary based on lofexdine tolerability, however on average subjects will be in a methadone withdrawal phase of the study for approximately 10 days) ] [ Designated as safety issue: No ]
    COWS Scores at Baseline (representing when a patient is on his/her normal methadone maintenance dose when withdrawal should be minimal or zero) will be compared to COWS Scores during methadone reduction phases of the study to determine how the intervention is affecting withdrawal. Smaller changes from baseline indicate better control of withdrawal symptoms.

  • Methadone Area Under the Curve (AUC) [ Time Frame: 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 ] [ Designated as safety issue: Yes ]
    AUC will be calculated for methadone at 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)

  • Lofexidine Area Under the Curve (AUC) [ Time Frame: plateau days pre-dose, 0.5, 1 , 2, 3, 4, and 5 hours post dose ] [ Designated as safety issue: Yes ]
    AUC will be calculated for lofexidine 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)

  • Change in Vital Signs [ Time Frame: 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)] ] [ Designated as safety issue: Yes ]
    Vital signs of subjects on methadone alone (baseline) will be compared to participant vital signs while taking methadone and the range of studied lofexidine doses.

  • Change in Adverse Events [ Time Frame: baseline and during treatment visit [participant time in the study will vary, however participants will be exposed to up 3 different lofexidine doses (escalating from 0.4 QID to 0.8 mg QID) over inpatient period of up to 21 days] ] [ Designated as safety issue: Yes ]
    Adverse Events in subjects on methadone alone (baseline) will be compared to participant adverse events while taking methadone and the range of studied lofexidine doses.


Enrollment: 27
Study Start Date: July 2012
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Lofexidine Titration in Methadone Maintained Subjects
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
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.
Placebo Comparator: Placebo titration in methadone maintained subjects
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
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.

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  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adult male and/or female, 18 to 60 years of age (inclusive).
  2. 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.
  3. Body mass index ≥ 18 and ≤ 35 (kg/m2).
  4. Normal screening results or abnormal results that have been deemed by the Investigator as clinically insignificant.
  5. Able to understand and willing to sign an informed consent form (ICF).
  6. 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.

Exclusion Criteria:

  1. 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.
  2. 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.
  3. History or presence of any degree of chronic obstructive pulmonary disease.
  4. History of suicidal ideations or depression requiring professional intervention including counseling or antidepressant medication over the past 12 months.
  5. Positive drug (urine)/alcohol (breath) test at screening or check-in excluding methadone. Subjects who have a positive test for heroin and benzodiazepines at the Screening Visit may be enrolled if the test is negative at check-in to the Inpatient Treatment Visit. Subjects who have a positive test for heroin or benzodiazepines at the Screening Visit must sign an ICF at check-in to the Inpatient Clinic Visit.
  6. Receiving methadone for pain management.
  7. Positive test for human immunodeficiency virus (HIV) or hepatitis B surface antigen (HBsAg). Subjects with a positive test for hepatitis C antibodies (HCV) may be enrolled if subject is asymptomatic.
  8. Estimated creatinine clearance < 80 mL/minute at screening (Cockcroft-Gault formula).
  9. AST, ALT, or alkaline phosphatase > 3.0 x upper limit of normal at screening or check-in.
  10. Amylase or lipase > 1.5 x upper limit normal at screening or check-in.
  11. Clinically significant out-of-reference range clinical chemistry values, with particular attention to potassium, magnesium, and calcium.
  12. History of hypotension.
  13. History of hypersensitivity or allergy to clonidine or any clonidine analogue.
  14. Use of any new prescription medication within 12 days prior to check-in.
  15. Use of any over-the-counter medication, including herbal products, within the 5 days prior to check-in. Up to 2 grams per day of acetaminophen is allowed at the discretion of the principal investigator or his designee.
  16. Use of any drug known to affect QTc within 30 days prior to check-in (tobacco and methadone excluded).
  17. Blood donation or significant blood loss within 30 days prior to check-in.
  18. Plasma donation within 7 days prior to check-in.
  19. Participation in another clinical trial within 30 days prior to check-in.
  20. Females who are pregnant or lactating.
  21. Participation in the lofexidine hydrochloride pilot protocol USWM-LX1-1005-1.
  22. Any other condition or prior therapy, which, in the opinion of the Investigator, would make the subject unsuitable for this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01650649

Locations
United States, Utah
Lifetree Clinical Research
Salt Lake City, Utah, United States, 84106
Sponsors and Collaborators
US WorldMeds LLC
Investigators
Study Director: Charles W. Gorodetzky, MD, PhD US WorldMeds
Study Director: James A Longstreth, PhD US WorldMeds
  More Information

No publications provided

Responsible Party: US WorldMeds LLC
ClinicalTrials.gov Identifier: NCT01650649     History of Changes
Other Study ID Numbers: USWM-LX1-1005-2, 1U01DA030916-01
Study First Received: July 9, 2012
Last Updated: January 15, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by US WorldMeds LLC:
lofexidine
methadone
interaction
pharmacodynamic
ECG
QTc

Additional relevant MeSH terms:
Substance Withdrawal Syndrome
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Clonidine
Lofexidine
Methadone
Adrenergic Agents
Adrenergic Agonists
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Analgesics
Analgesics, Opioid
Antihypertensive Agents
Antitussive Agents
Autonomic Agents
Cardiovascular Agents
Central Nervous System Agents
Central Nervous System Depressants
Molecular Mechanisms of Pharmacological Action
Narcotic Antagonists
Narcotics
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Respiratory System Agents
Sensory System Agents
Sympatholytics
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014