Pilot Study of Lofexidine and Methadone Pharmacodynamic Interaction in Methadone Maintained Patients
Condition: Opioid Dependence; Methadone Withdrawal Syndrome
MeSH terms: Opioid-Related Disorders; Substance Withdrawal Syndrome
Study type: Interventional
Phase: Phase 1

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; 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.
    

Detailed description: 
      This will be an open-label multiple ascending dose study to assess the safety, tolerability,
      and electrocardiographic effects of lofexidine in 6 methadone-maintained adult subjects. The
      study will include a Screening Visit, an Inpatient Treatment Visit, and a Follow-Up Visit.

      Subjects who are on a stable dose of methadone (80 - 120 mg/day) and who satisfy inclusion
      and exclusion criteria will be eligible for the study. Within 21 days of the Screening Visit,
      subjects will report to the inpatient study facility to begin the Inpatient Treatment Visit
      which will last between 10 to 27 days. This visit will include an inpatient check-in (1 day),
      Methadone Baseline (1 day), Initial Lofexidine Titration (up to 4 days), 1, 2 or 3 Lofexidine
      Plateaus (2 days each), Methadone Reduction (up to 11 days), and Methadone Re-Titration and
      Discharge (up to 4 days). The order of steps subjects will proceed through during the
      Inpatient Treatment Visit will vary depending on subjects' ability to titrate to a 0.8 mg QID
      dose of lofexidine and whether or not they experience opiate withdrawal during methadone
      reduction. Diagrams for the three scenarios that can occur with lofexidine titration are
      located in Figure 1, 2, and 3 in the body of the protocol.

      During the Methadone Baseline phase subjects will take a single daily dose of methadone at 1
      PM and undergo baseline study assessments including electrocardiogram (ECG) monitoring and
      blood collection for methadone pharmacokinetics. The next day subjects will proceed to the
      Initial Lofexidine Titration phase. Subjects will continue using their baseline methadone
      dose. Lofexidine will be initiated at 0.2 mg QID and titrated in daily increments of 0.2 mg
      QID to a total dose of 0.8 mg QID (3.2 mg/day), if tolerated by the subject. Lofexidine doses
      will escalate daily unless at any point the subject meets protocol-defined dose hold criteria
      (described below), which will trigger a reduction in dose to the previous highest tolerated
      dose. Once subjects have titrated to the 0.8 mg QID dose or once the highest tolerated dose
      of lofexidine has been determined, they will proceed to a 2-day Lofexidine Plateau phase
      during which they will continue to receive their methadone maintenance dose. If the subject
      is not able to titrate up to 0.8 mg QID, the subject will continue to receive their highest
      tolerated dose in equal increments (eg, 0.2, 0.4, or 0.6 mg QID at 8AM, 1PM, 6PM, 11PM) for
      both days of the plateau. If the subject tolerates 0.8 mg QID lofexidine, on the first day
      they will receive 0.8 mg QID lofexidine according to the normal dosing schedule. On the
      second day the lofexidine dosing schedule will be modified with subjects receiving a 0.2 mg
      increase of the 1 PM lofexidine dose (1 mg dose) and a 0.2 mg reduction in the subsequent
      lofexidine dose (0.6 mg dose) with the other 2 doses of 0.8 mg (total dose of 3.2 mg/day). On
      the second day of the Lofexidine Plateau phase, subjects will undergo electrocardiogram (ECG)
      monitoring and blood collection for methadone and lofexidine pharmacokinetics.

      Subjects who are unable to titrate to the 0.8 mg QID lofexidine dose while receiving their
      full dose of methadone will undergo a methadone dose reduction of 50%, or if necessary a dose
      reduction of 100%, and will continue lofexidine titration by adding an incremental 0.2 mg QID
      to the previously established tolerated dose up to the maximum 0.8 mg QID dose. During these
      subsequent titration attempts lofexidine doses will escalate daily unless in any event a
      subject meets protocol defined dose-hold criteria (described below), which will trigger a
      reduction in dose to the previous highest tolerated dose and will require the Lofexidine
      Plateau procedures described above to be repeated while maintaining the subject on their
      newly reduced methadone dose (eg, 50% of their maintenance dose and, if 0.8 mg QID is not
      achieved at the first reduction, again at 0% of their maintenance dose for 2 days followed by
      reinstatement of 25% of their starting dose).

      Subjects who are able to titrate to the 0.8 mg QID lofexidine dose while receiving their full
      dose of methadone will continue to receive the maximum lofexidine dose while undergoing a 4
      day Methadone Reduction at 50% of their maintenance dose to evaluate lofexidine's impact on
      the withdrawal syndrome.

      During Methadone Reduction (whether for subjects entering an experimental 4-day 50%
      withdrawal phase at the tolerated 0.8 mg QID lofexidine dose or for subjects continuing
      lofexidine titration at 50% and 100% methadone reductions), assessments of opiate withdrawal
      will be performed using the Clinical Opiate Withdrawal Scale (COWS) and the Short Opiate
      Withdrawal Scale (SOWS).

      Following completion of the Lofexidine Plateau (repeated as necessary) and Methadone
      Reduction, subjects will begin the Methadone Re-Titration and Discharge phase during which
      lofexidine will be discontinued (except to treat withdrawal symptoms as necessary) and
      methadone will be re-titrated to the starting dose (or to a higher or lower dose relative to
      baseline as medically indicated at the discretion of the investigator). Following successful
      methadone titration and completion of study assessments, subjects will be discharged from the
      inpatient study clinic.

      Subjects will return to the study clinic for a follow-up visit 7 days (±2 days) following
      clinic discharge for safety follow-up and adverse event collection. Subjects will be
      discharged from the study at this time unless they are medically unstable on their dose of
      methadone. Subject may be medically followed at a regular interval, as determined by the
      investigator, until the subject is considered sufficiently stable for study discharge.

      Subjects who withdraw consent or meet any one of the following study termination criteria
      prior to completion of the study will be withdrawn:

        1. Cardiovascular events including the following:

             1. Systolic blood pressure <70 mmHg and >20% below screen value;

             2. Diastolic blood pressure <40 mmHg and >20% below screen value:

             3. Heart rate <40 bpm and >20% below screen value;

             4. QTc >500 msec or >25% above screen value for both males and females;

             5. Syncope. *ECGs and vital signs may be repeated as appropriate to confirm values and
                rule out extraneous results.

        2. Serious medical problems thought to be related or unrelated to the study medications.

        3. Intercurrent illness or medical complications that, in the opinion of the site
           investigator, preclude safe administration of study medications.

      At the time of termination from the study, subjects will be discontinued from lofexidine;
      however, they may remain inpatient for up to 4 days while their methadone maintenance dose is
      re-titrated to their pre-study maintenance dose.
    

Intervention name(s): Lofexidine HCl
Intervention type(s): Drug
Intervention description(s): Lofexidine 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.
Intervention MeSH terms: Lofexidine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: lofexidine; methadone; interaction; pharmacodynamic; ECG; QTc