Single and Multiple Rising Dose Study of Safety and PK of Metyrapone/Oxazepam Combination (EMB-001)

Study Overview
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Brief Summary
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This is a study of EMB-001 (a combination of two FDA-approved drugs, metyrapone and oxazepam) in otherwise healthy adults who are regular cigarette smokers. There will be 3 groups of 8 subjects; in each group, 6 subjects will get the drug combination and 2 will get placebo. Neither the subjects nor the study personnel will know who got drug and who got placebo (double-blind). In the first group the drug doses will be low, and they will be increased in the second and third groups. Subjects will receive a single dose on Day 1, followed 24 hours later by the start of doses twice daily for 7 days, and then a final morning dose on the last day. The levels of the drugs in the blood will be assessed by repeated blood draws after the first day and after the end of dosing. Safety will be assessed after the single dose and repeated dosing. Effects of study drug on smoking and craving cigarettes will be assessed at the end of repeated dosing. The hypothesis is that this drug combination will be safe, with relatively few side effects.

Detailed Description
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This study is a Phase 1, double blind, single and multiple rising dose tolerance study of EMB-001 (metyrapone/oxazepam combination) in otherwise healthy adults who have tobacco use disorder. There will be 3 cohorts, each with 8 subjects (6 active: 2 placebo), for a total of 24 subjects. During the treatment period, subjects will receive a single dose of EMB 001 on Day 1, followed 24 hours later by the start of multiple doses twice daily for 7 days, and then a final morning dose on the last dosing day (Day 9). This design allows for characterization of EMB-001 single dose PK for 24 hours, followed by assessment of repeat dose PK in the multiple-dose phase. Safety will be assessed after the single dose and repeated dosing. Effects of study drug on smoking and craving cigarettes will be assessed at the end of repeated dosing. Later studies may also assess the efficacy of this drug combination in treating cocaine use disorder, tobacco use disorder, and/or other disorders.

Official Title
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Phase 1 Combined Single and Multiple Rising Dose Study of the Safety and Pharmacokinetics of Metyrapone/Oxazepam Combination (EMB-001)

Conditions
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Cocaine Use Disorder, Tobacco Use Disorder

Intervention / Treatment
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* Drug: metyrapone & oxazepam
* Drug: metyrapone & oxazepam
* Drug: metyrapone & oxazepam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females of Non-Childbearing Potential age 18-65 Have provided written informed consent prior to any study procedures Are willing and able to comply with all aspects of the protocol Normal or clinically acceptable screening electrocardiogram (ECG) Normal blood pressure (systolic: 90-140 mmHg; diastolic 50-90 mmHg) and heart rate (50-100 bpm) Smoke at least 10 cigarettes per day (for approximately 1 year or longer) Body mass index > 18.5 and < 35 Exclusion Criteria: Known hypersensitivity to or intolerance of oxazepam or metyrapone, or any benzodiazepine Subjects with a low out-of-range serum cortisol value at screening or subjects who, in the investigator's opinion, have a heightened likelihood of having adrenal insufficiency. Subjects who have a positive urine drug screen for illegal drugs or other drugs with a high potential for abuse (other than nicotine). Inability to communicate or cooperate with the investigator History of drug dependence (except nicotine) or psychiatric illness within the past 2 years. Subjects with any history of adrenal insufficiency or other adrenal, hypothalamic, or pituitary disorders. History of asthma or other respiratory disease, neurologic or neuromuscular disease, or hypotension or cardiovascular disease, that may, in the opinion of the investigator, impact any study procedures or measures, or compromise the safety of the subject. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and, in the judgment of the Investigator or Sponsor, would make the subject inappropriate for entry into this trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Subjects will receive capsules containing no active pharmaceutical ingredients. | Drug: Placebo<br>* Each cohort will have 2 subjects receiving placebo<br>* Other names: All Cohorts;|
| Active Comparator: Low Dose (Cohort 1)<br>270 mg metyrapone and 12 mg oxazepam, given once for the single-dose phase of the study, followed by BID dosing for approximately one week | Drug: metyrapone & oxazepam<br>* 6 subjects will receive active study drug (a low dose combination of metyrapone & oxazepam) and 2 subjects will receive placebo.<br>* Other names: Cohort 1;|
| Active Comparator: Medium Dose (Cohort 2)<br>540 mg metyrapone and 24 mg oxazepam, given once for the single-dose phase of the study, followed by BID dosing for approximately one week | Drug: metyrapone & oxazepam<br>* 6 subjects will receive active study drug (a medium dose combination of metyrapone & oxazepam) and 2 subjects will receive placebo.<br>* Other names: Cohort 2;|
| Active Comparator: High Dose (Cohort 3)<br>720 mg metyrapone and 24 mg oxazepam, given once for the single-dose phase of the study, followed by BID dosing for approximately one week | Drug: metyrapone & oxazepam<br>* 6 subjects will receive active study drug (a high dose combination of metyrapone & oxazepam) and 2 subjects will receive placebo.<br>* Other names: Cohort 3;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety/Tolerability based on multiple safety parameters (adverse events (AE), physical examinations, vital signs, 12-lead ECG, Sheehan Suicidality Tracking Scale (S STS) and laboratory tests) | Safety will be assessed through monitoring of adverse events (AE), physical examinations, vital signs, 12-lead ECG, Sheehan Suicidality Tracking Scale (S STS) and laboratory tests. | Daily on Days 1-12, and on Day 17. Study Completion occurs on Day 17. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Plasma PK parameters will be serially assessed for oxazepam, metyrapone, and for the primary metabolite of metyrapone, metyrapol) | Plasma PK parameters will be serially assessed for oxazepam, metyrapone, and for the primary metabolite of metyrapone, metyrapol. | After single- and multiple-dosing- Samples will be drawn on Day 1 and Day 10 at the following times Pre-dose, .25, .5, .75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, & 48 hours. |