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

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:
2. Systolic blood pressure <70 mmHg and >20% below screen value;
3. Diastolic blood pressure <40 mmHg and >20% below screen value:
4. Heart rate <40 bpm and >20% below screen value;
5. QTc >500 msec or >25% above screen value for both males and females;
6. Syncope. *ECGs and vital signs may be repeated as appropriate to confirm values and rule out extraneous results.
7. Serious medical problems thought to be related or unrelated to the study medications.
8. 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.