A Study Evaluating the Relative Bioavailability of Lofexidine Granules for Reconstitution Compared to LUCEMYRA (Lofexidine) Tablets and the Effect of Food on the Bioavailability of the Lofexidine Granules for Reconstitution

Study Overview
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Brief Summary
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The purpose of this open-label, single-dose, randomized, three-treatment, three-period, four-sequence, crossover study is to evaluate the relative bioavailability of a test formulation of lofexidine granules for reconstitution (oral) and LUCEMYRA tablets under fasted conditions and to evaluate the effect of food on the relative bioavailability of lofexidine granules for reconstitution (oral) when administered under fed compared to fasted conditions.

Official Title
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A Study to Evaluate the Relative Bioavailability of a Test Formulation of Lofexidine Granules for Reconstitution and the Effect of Food on the Bioavailability of the Test Formulation in Healthy Adult Subjects

Conditions
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Normal Healthy Volunteers

Intervention / Treatment
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* Drug: Lofexidine (granules for reconstitution)
* Drug: LUCEMYRA (lofexidine) tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Males and females, 18-50 years of age, inclusive, with a Body Mass Index (BMI) of 20.0-35.0 kg/m², inclusive. Female subjects must meet at least one of the following criterion: Agree to abstain from sexual intercourse from screening and throughout the duration of the study. Have used and agree to continue to use a reliable method of contraception (e.g., condom with spermicide, IUD, hormonal contraceptives) for at least 30 days before initial dosing and throughout the duration of the study. Surgically sterile (bilateral oophorectomy or hysterectomy, bilateral tubal ligation or Essure® device placement at least 3 months prior to initial dosing). At least 1 year postmenopausal and have a documented FSH level ≥ 40 mIU/mL at screening. Good health as determined by lack of clinically significant abnormalities in health assessments performed at screening. Signed and dated informed consent form, which meets all criteria of current FDA regulations. Exclusion Criteria Females who are pregnant, lactating, or likely to become pregnant during the study. History of allergy or sensitivity to lofexidine or any component of the study drug or history of any drug hypersensitivity or intolerance which, in the opinion of the Investigator, would compromise the safety of the subject or the study. Significant history or current evidence of chronic infectious disease, system disorders, or organ dysfunction, especially cardiovascular disorders (e.g., severe coronary insufficiency, recent myocardial infarction [within 1 year before initial dosing], cerebrovascular disease), respiratory disorders, congenital long QT syndrome, diabetes, hepatic or renal disorders (e.g., chronic renal failure). Pulse < 50 bpm or symptomatic bradycardia, as determined by the Investigator. Clinically significant history of hypotension, as determined by the Investigator, or has a sitting/supine systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 60 mmHg, or hypertension, as determined by the Investigator, or has sitting/supine systolic blood pressure > 190 mmHg and/or diastolic > 95 mmHg; determined at screening. Experiences reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing from a resting (sitting or supine) position; determined at screening. 12-lead ECG, conducted in triplicate, considered by the Investigator to be clinically significant (e.g., second or third degree heart block, uncontrolled arrhythmia) or has a QTcF (Fridericia's correction) interval > 440 msec in 2 of the 3 ECGs performed; determined at screening. Clinically significant history or presence of any gastrointestinal disease or history of malabsorption within the last year, as determined by the Investigator. History of any psychiatric disorders occurring within the last two years that required the subject to be hospitalized or treated with medication. Subject has history of suicidality based on responses provided on the Columbia-Suicide Severity Rating Scale (C-SSRS), or is at risk for self-harm or harm to others based on clinical interview, at the discretion of the Investigator. Ingestion of grapefruit-containing food or beverages (e.g., Fresca®) within 7 days before dosing. Drug or alcohol addiction requiring treatment in the 12 months before initial dosing. History of excessive alcohol consumption (on average more than 14 units of alcohol/week) during the past 12 months. Positive test results for HIV, Hepatitis B surface antigen, or Hepatitis C antibody. Positive test results for drugs of abuse (benzodiazepines, cocaine, cannabinoids/THC, opiates and at screening only: amphetamines, barbiturates, methadone and phencyclidine).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lofexidine (granules for reconstitution), fasted<br>Participants will be administered lofexidine granules for reconstitution following an overnight fast of at least 10 hours. | Drug: Lofexidine (granules for reconstitution)<br>* All subjects will be administered one 0.36 mg dose of lofexidine granules for reconstitution.<br>|
| Active Comparator: LUCEMYRA (lofexidine) tablets, fasted<br>Participants will first be administered LUCEMYRA (lofexidine) tablets following an overnight fast of at least 10 hours | Drug: LUCEMYRA (lofexidine) tablets<br>* All subjects will be administered one 0.36 mg dose of LUCEMYRA (lofexidine) tablets.<br>|
| Experimental: Lofexidine (granules for reconstitution), fed<br>Participants will first be administered lofexidine granules for reconstitution, 30 minutes following a standardized breakfast preceded by an overnight fast of at least 10 hours. | Drug: Lofexidine (granules for reconstitution)<br>* All subjects will be administered one 0.36 mg dose of lofexidine granules for reconstitution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Maximum Plasma Concentration (Cmax) | The peak exposure plasma concentrations (Cmax) of lofexidine were observed and measured. | Mean from Day 1 through Day 3 for Periods I, II, III. | 
| Time to Maximum Plasma Concentration (Tmax) | Time to peak plasma concentration (h) collection time at which Cmax is first observed. | Day 1 through Day 3 for Periods I, II, III. | 
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-t) | Areas under the plasma concentration-time curve from time zero to the time of last measurable concentration (AUC0-t) | Day 1 through Day 3 for Periods I, II, III. | 
| Area Under the Plasma Concentration-time Curve From Time Zero to Time Infinity (AUC0-∞) |  | Mean from Day 1 through Day 3 for Periods I, II, III. | 
| First-order Terminal Rate Constant (λz) |  | Mean from Day 1 through Day 3 for Periods I, II, III. | 
| First-order Terminal Half-life (T½) |  | Mean from Day 1 through Day 3 for Periods I, II, III. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events (AEs) | Number of Subjects dosed for each Treatment groups: Treatment A = 15 subjects dosed; Treatment B = 16 subjects dosed; Treatment C = 15 subjects dosed | Total from occurrences assessed daily after each dosing for Periods 1-3, as well as end of study (22 days) |