Pilot Study of Lofexidine and Methadone Pharmacodynamic Interaction in Methadone Maintained Patients
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 2/24/2018 |
| Start Date: | February 2012 |
| End Date: | April 2012 |
A Pilot, Multiple Ascending Dose Study to Assess the Safety, Tolerability, and Electrocardiographic Effects of Lofexidine When Administered Orally to Methadone Maintained Adult Subjects
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.
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.
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.
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.
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 (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. 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.
We found this trial at
1
site
Click here to add this to my saved trials
