Pilot 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:
NCT01558934
First received: February 14, 2012
Last updated: April 16, 2012
Last verified: April 2012
  Purpose

The primary objective of this study is to assess QTc (an interval of the heart rythym) 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; and to describe effects on opiate withdrawal when lofexidine is introduced following a 50% or 100% methadone dose reduction, as required to elicit a withdrawal response. The investigators hypothesize that while both agents 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
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot, 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 and each day the lofexidine dose is esalated (participant time in the study will vary based on tolerability, however the participants will be exposed to up four different lofexidine doses (escalating from 0.2 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 each day the lofexidine dose is esalated (participant time in the study will vary based on tolerability, however the participants will be exposed to up four different lofexidine doses (escalating from 0.2 QID to 0.8 mg QID) ] [ 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: 6
Study Start Date: February 2012
Study Completion Date: April 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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 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. If the therapeutic dose is not reached under 50% methadone reduction conditions, the methadone dose will be further reduced to 0 mg for 2 days followed by reintroduction of 25% of the starting dose on the 3rd day, and on such 3rd day lofexidine titration will resume again.
Drug: Lofexidine HCl
Lofexidinne HCl 0.2 mg tablets titrated in ascending doses of 0.2 mg QID (e.g. Day 1 0.2 mg QID, Day 2 0.4 QID, etc)as described in the treatment arm.

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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, 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 recumbent values
    • prior history of myocardial infarction (MI) or evidence of prior MI on ECG* *ECGs and vitals may be repeated as appropriate in order to confirm values and rule out extraneous results.
  2. History or presence of significant cardiovascular, 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.
  5. Positive drug (urine)/alcohol (breath) test at Screening Visit or check-in to the Inpatient Clinic Visit 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 (Cockroft-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. History of hypotension.
  12. History of hypersensitivity or allergy to clonidine or any clonidine analogue.
  13. Use of any new prescription medication within 12 days prior to check-in.
  14. 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 PI/PI‟s designee.
  15. Use of any drug known to affect QTc within 30 days prior to check-in (tobacco excluded).
  16. Blood donation or significant blood loss within 30 days prior to check-in.
  17. Plasma donation within 7 days prior to check-in.
  18. Participation in another clinical trial within 30 days prior to check-in.
  19. Females who are pregnant or lactating.
  20. Any other condition or prior therapy, which, in the opinion of the Investigator, would make the subject unsuitable for this study.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01558934

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: NCT01558934     History of Changes
Other Study ID Numbers: USWM-LX1-1005-1, 1U01DA030916-01
Study First Received: February 14, 2012
Last Updated: April 16, 2012
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
Opioid-Related Disorders
Substance-Related Disorders
Mental Disorders
Methadone
Clonidine
Lofexidine
Analgesics, Opioid
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Central Nervous System Depressants
Antitussive Agents
Respiratory System Agents
Narcotics
Antihypertensive Agents
Cardiovascular Agents
Narcotic Antagonists
Adrenergic alpha-2 Receptor Agonists
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Sympatholytics
Autonomic Agents

ClinicalTrials.gov processed this record on July 29, 2014