Pharmacokinetic & Pharmacodynamic Interaction of Lofexidine and Buprenorphine in Buprenorphine Maintained Patients
Condition: Opioid Dependence; Buprenorphine 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 lofexidine related effects on QTc (an
      interval of the heart rhythm) in subjects receiving buprenorphine maintenance. 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
      buprenorphine; to describe effects on opiate withdrawal when lofexidine is introduced
      following a 50% buprenorphine dose reduction, as required to elicit a withdrawal response;
      and to evaluate QTc interaction effects of lofexidine compared with placebo. The
      Investigators hypothesize that while lofexidine is 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 buprenorphine
      maintenance dose is lowered to elicit withdrawal.
    

Detailed description: 
      This will be a randomized, double-blind, placebo-controlled multiple ascending dose study to
      assess the safety, tolerability, and electrocardiographic effects of lofexidine in 30
      buprenorphine-maintained adult subjects. The study will include a Screening Visit, an
      Inpatient Treatment Visit, and a Follow-Up Visit. Subjects will be randomized in 4:1 ratio to
      receive up to 4 tablets of lofexidine (0.2 mg/tablet) QID or 4 tablets matching placebo QID.

      Subjects who are on a stable dose of total daily sublingual buprenorphine 16-24 mg/day with
      or without naloxone (Suboxone® or Subutex®, respectively), 16 - 24 mg/day, and who satisfy
      inclusion and exclusion criteria will be eligible for the study. Subjects who are eligible
      for the study will be encouraged to begin shifting their medication dose to a total daily
      dose at 2 PM in anticipation of the study dosing schedule during the Inpatient Treatment
      Visit. Subjects who are receiving Suboxone tablets or Subutex at study enrollment will be
      converted to Suboxone film at the inpatient check-in and will receive Suboxone sublingual
      film throughout 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
      approximately 11 to 21 days. This visit will include an inpatient check-in (1 day),
      Buprenorphine Baseline (1 day), Initial Lofexidine Titration (3 to 5 days), 1 or 2 Lofexidine
      Plateaus (2 to 4 days), Buprenorphine Reduction (2 to 6 days) and Buprenorphine Re-Titration
      and Discharge (2 to 4 days). The order of steps subjects will proceed through during the
      Inpatient Treatment Visit will vary depending on whether subjects are able to titrate to the
      highest dose of lofexidine or placebo during the Initial Lofexidine Titration. The highest
      dose of lofexidine (or placebo) will be 4 tablets QID (0.2 mg lofexidine per tablet or
      placebo) for a total daily lofexidine dose of 16 tablets (3.2 mg or placebo).

      During the Buprenorphine Baseline phase subjects will take a single daily dose of
      buprenorphine at 2 PM. Buprenorphine Baseline Day study assessments will begin at
      approximately 7 AM and include electrocardiogram (ECG) monitoring, blood collection for
      buprenorphine pharmacokinetics, and opiate withdrawal assessments (Clinical Opiate Withdrawal
      Scale, COWS and Short Opiate Withdrawal Scale, SOWS). The next day subjects will proceed to
      the Initial Lofexidine Titration phase. Subjects will continue using their baseline
      buprenorphine dose. Lofexidine will be initiated at 2 tablets (0.4 mg or placebo) QID and
      titrated in daily increments of a single tablet (0.2 mg or placebo) QID to a total daily dose
      of 0.8 mg QID (or placebo), 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 (or to the 1
      tablet dose, 0.2 mg or placebo, if subjects cannot tolerate the initial 2 tablets, 0.4 mg or
      placebo). Once subjects have titrated to the highest dose (ie, 4 tablets QID) or once the
      highest tolerated dose has been determined, they will proceed to a 2-day Lofexidine Plateau
      phase during which they will continue to receive their buprenorphine maintenance dose. If the
      subject is unable to titrate up to 4 tablets QID (0.8 mg or placebo), the subject will
      continue to receive their highest tolerated dose in equal increments (eg, 2 or 3 tablets QID
      at 8AM, 1PM, 6PM, 11PM) for both days of the plateau. Subjects who tolerate 4 tablets QID
      (0.8 mg or placebo) on the first day will receive the 4 tablets QID (0.8 mg or placebo)
      according to the normal dosing schedule. On the second day, the lofexidine dosing schedule
      will be modified with subjects receiving a 1-tablet increase (ie, 0.2 mg or placebo) of the 1
      PM lofexidine dose (5 tablets: 1 mg or placebo) and a 1-tablet reduction (0.2 mg or placebo)
      in the subsequent lofexidine dose (3 tablets: 0.6 mg or placebo) with the other 2 doses of 4
      tablets (0.8 mg or placebo) for a total daily dose of 16 tablets (3.2 mg/day or placebo). On
      the second day of the Lofexidine Plateau phase, subjects will undergo ECG monitoring and
      blood collection for buprenorphine and lofexidine pharmacokinetics. COWS and SOWS assessments
      will be performed on both days of the Lofexidine Plateau.

      Subjects who are titrated to a daily dose of 4 tablets (0.8 mg or placebo) QID while
      receiving their full dose of buprenorphine will undergo a 4-day buprenorphine dose reduction
      of 50% while continuing to take lofexidine or placebo at a daily dose of 16 tablets to
      evaluate the effects of lofexidine on buprenorphine withdrawal signs and symptoms. These
      subjects who complete the initial Lofexidine Plateau at a dose of 0.8 mg lofexidine (or
      placebo) QID and who reach a COWS of 5 or greater prior to the fourth day of the reduced
      buprenorphine dose administration may proceed early to Buprenorphine Re-titration and
      Discharge at the Investigator's discretion. If the COWS score does not reach 5 within 4 days,
      the subject will proceed to Buprenorphine Re-titration and Discharge.

      Subjects who are unable to titrate to the highest lofexidine dose (4 tablets: 0.8 mg or
      placebo QID) while receiving their full dose of buprenorphine will undergo a buprenorphine
      dose reduction of 50% for up to 6 days while continuing to receive their highest tolerated
      dose of lofexidine from the initial titration. On the fourth day (or earlier at the
      investigator's discretion based on withdrawal response), lofexidine titration will resume by
      adding an incremental 1 tablet (0.2 mg or placebo) QID to the previously established
      tolerated dose up to the maximum 4 tablet (0.8 mg or placebo) QID dose. During these
      subsequent titration attempts lofexidine (or placebo) doses will escalate daily beginning on
      the fourth day of the reduction (or earlier based on discretion of the investigator) 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 buprenorphine dose (eg, 50% of their maintenance dose). Subjects who are
      unable to titrate to a higher lofexidine dose during the 50% Buprenorphine Reduction than the
      dose they titrated to during the Initial Lofexidine Titration will not repeat the Lofexidine
      Plateau procedures. During Buprenorphine Reduction, COWS and SOWS assessments of opiate
      withdrawal will be performed. On days when the lofexidine dose is increased, holter
      monitoring and pharmacokinetic (PK) sampling will be done for those subjects who did not
      titrate all the way up to the maximum dose of lofexidine during the initial titration period.

      Following completion of the Lofexidine Plateau (repeated as necessary) and Buprenorphine
      Reduction, subjects will begin the Buprenorphine Re-Titration and Discharge phase during
      which lofexidine or placebo will be discontinued and buprenorphine 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). Lofexidine may be used to treat withdrawal symptoms, if
      necessary. Following successful buprenorphine 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
      buprenorphine. 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. Study termination criteria will apply
      only to pre-dose sitting vital signs and the daily safety ECG readings (excluding HR).
      Baseline values for vital signs and ECG readings refer to values obtained at the time
      subjects are admitted to the clinic. 1.Cardiovascular events including the following*: a.
      Systolic blood pressure (SBP) <70 mmHg and >20% below baseline value, b. Diastolic blood
      pressure (DBP) <40 mmHg and >20% below baseline value (if subject is asymptomatic, DBP
      termination criteria <30 mmHg), c. Heart rate <40 bpm and >20% below baseline value (if
      subject is asymptomatic, HR termination criteria <30 bpm), d. Changes in QTcF that meet any
      of the following criteria: i.QTcF >500 ms in females or QTcF>480 ms in males, ii. QTcF >25%
      above baseline value for both males and females, iii. QTcF<500 ms in females or QTcF <480 ms
      in males with a persistent (ie, greater than 24 hours) increase in QTcF value >60 ms from
      baseline accompanied by abnormal electrolytes (ie, potassium and sodium), e. Absolute QRS>120
      ms along with a 25% increase from baseline, f. Absolute PR>240 ms along with a 25% increase
      from baseline, g. Syncope h. Clinically significant arrhythmia (including telemetry
      indication of ventricular tachycardia, ventricular fibrillation, Torsade de Pointes, 2nd
      degree AV block)

      *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 or
      placebo; however, they may remain inpatient for usually up to 4 days, with extension allowed
      as deemed necessary per Investigator, while their buprenorphine maintenance dose is
      re-titrated to their pre-study maintenance dose.
    

Intervention name(s): Lofexidine HCl; Lofexidine-matching sugar pill
Intervention type(s): Drug; Drug
Intervention description(s): Lofexidine HCl 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 mg (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.; 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.
Intervention MeSH terms: Lofexidine; Clonidine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: lofexidine; buprenorphine; interaction; pharmacodynamic; ECG; QTc