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

• Status: Completed
• Trial end date: 2012-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: US WorldMeds LLC
• Collaborator: National Institute on Drug Abuse (NIDA)
• Treatments: Clonidine; Lofexidine; Methadone

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.