Open-Label, Safety Study of Lofexidine

Study Overview
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Brief Summary
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The purpose of this Phase 3 open-label treatment study is to evaluate the safety and effectiveness of lofexidine at a clinically relevant dose to alleviate symptoms of acute withdrawal from any opioid, including methadone and buprenorphine. This study will take place in a variety of clinical scenarios, both in-clinic and outpatient settings.

Detailed Description
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Eligible subjects (person seeking treatment for partial or total opioid withdrawal) enrolled in this study are required to take lofexidine for a minimum of 7 days.

Official Title
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A Phase 3, Open-Label, Safety Study of Lofexidine

Conditions
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Opioid Withdrawal

Intervention / Treatment
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* Drug: Lofexidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or Female at least 18 years of age Must be able to verbalize understanding of the consent form, able to provide written informed consent, and verbalize willingness to complete study procedures Must have current dependence, according to the Mini International Neuropsychiatric Interview (M.I.N.I.), on any opioid (including methadone and buprenorphine maintenance treatment) Must be seeking treatment for partial or total withdrawal from current opioid and expected, as determined by the Principal Investigator, to benefit from lofexidine treatment for at least 7 days at clinically relevant doses. This can include a variety of clinical situations where opioid withdrawal illness is likely to occur including abrupt and total withdrawal (including from methadone and buprenorphine), agonist-assisted total withdrawal, dose reduction of maintenance treatment (e.g., methadone, buprenorphine) and transition from an opioid agonist to naltrexone or buprenorphine maintenance Must have Urine toxicology screen result of positive for opioid(s) relevant to the subject's withdrawal treatment goal If female and of childbearing potential, subject must agree to use of one of the following methods of birth control including oral contraceptives, patch, barrier (diaphragm, sponge or condom) plus spermicidal preparations, intrauterine contraceptive system, levonorgestrel implant, medroxyprogesterone acetate contraceptive injection, complete abstinence from sexual intercourse, hormonal vaginal contraceptive ring or surgical sterilization or partner sterile (with documented proof) Exclusion Criteria: Female subject who is pregnant or lactating History of very serious medical illness not under control including, but not limited to, active self-reported acquired immune deficiency syndrome (AIDS) or self-reported human immunodeficiency virus (HIV) positive status and taking retroviral medications currently or within the past 4 weeks and/or having an unstable psychiatric condition. These conditions will be determined at Screening by medical history, physical examination, 12 lead electrocardiogram (duplicate), clinical laboratory tests for infectious diseases, and a tuberculin test Current dependence (based on the M.I.N.I.) on any psychoactive substance (excluding caffeine, nicotine, and the subject's current opioid-dependence agent, which can include methadone and buprenorphine, for example, in agonist-maintained subjects) that requires detoxification or dose reduction as part of the pre-defined individual subject withdrawal treatment goal Have participated in an investigational drug study within the past 30 days Have a history of lofexidine exposure in a prior clinical trial or otherwise Have an abnormal cardiovascular exam at screening Any subject that requires tricyclic antidepressants, which may reduce the efficacy of imidazoline derivatives and/or beta-receptor blockers, to avoid the risk of excessive bradycardia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Open Label Lofexidine<br>During this open-label study, subjects will be given the option to receive lofexidine tablets for 7 days and up to 14 days if requested. | Drug: Lofexidine<br>* All enrolled subjects will take lofexidine orally for 7 days, starting on Day 1 at a dose of 3.2 mg per day (0.8 mg QID), with lowering of the dose allowed to 2.4 mg daily (0.6 mg QID) if required for tolerability based on the subject's individual treatment goal and response per clinical judgment of the Principal Investigator.<br>* Other names: Lofexidine hydrochloride (HCL);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Occurrence of Treatment Emergent Adverse Events (TEAEs) | Subjects with at least 1 TEAE occurring on days 1-14. | Days 1-14 | 
| Overall Occurrence of Serious Treatment Emergent Adverse Events (Serious TEAEs) |  | Days 1-14 | 
| Overall Treatment Emergent Adverse Events (TEAEs) by Severity |  | Days 1-14 | 
| Occurrence of Per Protocol Adverse Events of Special Interest (AESI) |  | Day 1 to Day 14 | 
| Occurrence of Adverse Events (AEs) Not Related to Opioid Withdrawal |  | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Seated Systolic Blood Pressure (mmHg): Vital Sign | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Standing Systolic Blood Pressure (mmHg): Vital Sign | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Seated Diastolic Blood Pressure (mmHg): Vital Sign | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Standing Diastolic Blood Pressure (mmHg): Vital Sign | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Seated Pulse (Bpm): Vital Signs | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Mean Observed and Change From Screening in Standing Pulse (Bpm): Vital Signs | Baseline vital signs were defined by the assessment value at screening when subjects were not experiencing opioid withdrawal to reduce the potential for variability from the effects of different states of withdrawal that may have been present before dosing on Day 1. Overall screening values are captured in the column Inpatient: Pre 8AM; these values were recorded at various times for each participant during the screening visit, not necessarily at 8AM. Serial vital sign assessments required for inpatient visits on days 1-3, either inpatient or outpatient for days 4-7, and outpatient only for days 8-14. Day 14 only required pre-dose vital signs measurement. Day 1 Change, Pre 8AM was prior to the first dose. | Day 1 to Day 14 | 
| Columbia Suicide Severity Rating Scale Questionnaire (C-SSRS): Suicidal Ideation and Behavior Numbers | The C-SSRS measures both suicidal ideation and suicidal behavior and will be completed to assess lifetime suicidality before first dose of study drug, 3.5 hours after first daily dose of study drug on in-clinic treatment days, and then once a day before dosing during outpatient treatment days. C-SSRS will also be assessed at end of study/discontinuation. | Day 1 to Day 14 | 
| Clinical Laboratory Test Change From Baseline: Hematology | Hematology Parameters with Shifts in ≥3% of Subjects from Screening to End of Study | Day 1 to Day 14 | 
| Clinical Laboratory Test Change From Baseline: Chemistry | Chemistry Parameters with Shifts in ≥3% of Subjects from Screening to End of Study | Day 1 to Day 14 | 
| Clinical Laboratory Test Change From Baseline: Urinalysis |  | Day 1 to Day 7 | 
| Safety Electrocardiograms (ECG) Evaluation Shift From Baseline to Post Dose and End of Study | For each 12-lead ECG obtained during the study, the investigator made an overall interpretation of the ECG (normal, abnormal NCS, and abnormal CS). Shifts from normal at baseline to abnormal NCS and abnormal CS at the end of study predose and postdose assessments were summarized. | Day 1 and Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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detoxification, agonist taper, methadone step down, buprenorphine step down, opioid withdrawal syndrome