A Study of Metyrapone and Oxazepam Combination Product (EMB-001) and Cocaine

Study Overview
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Brief Summary
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EMB-001 is a combination of 2 drugs: the cortisol synthesis inhibitor, metyrapone (Metopirone®), and the benzodiazepine receptor agonist, oxazepam (original trade name Serax®; now marketed as oxazepam (generic) only). This Phase 1b cocaine interaction study is being conducted in order to assess the safety and PK of EMB-001 and cocaine in combination.

Detailed Description
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This is a single center, randomized, double-blinded, multiple-dose, PLB controlled, 2-period, 4-sequence, crossover study design. After establishing eligibility approximately 16 subjects with cocaine use disorder will be randomized to one of four sequences. Treatment periods will be separated by a 7-day in-patient washout period. EMB-001/PLB will be orally administered for 7 consecutive days, BID for 6 days (starting on Day 1 and Day 15) followed on the last day (Day 7 and Day 21) by one EMB-001/PLB oral dose in the morning. Infusion of 40 mg IV cocaine and IV saline-to-match cocaine infusion will be administered in a randomized order, 2 hours apart, starting 3 hours after the last morning EMB-001/PLB oral administration. The subjects will be discharged from the research clinic 2 days after the last dose of cocaine, and will have a follow-up visit 7 days after last dose.

Official Title
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A Phase 1b, Randomized, Double-Blinded, Multiple-Dose, Placebo Controlled, Crossover Study To Evaluate The Safety, Tolerability And Pharmacokinetic Effects Of A Metyrapone And Oxazepam Combination (EMB-001) When Co-Administered With Cocaine

Conditions
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Cocaine Use Disorder

Intervention / Treatment
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* Drug: EMB-001
* Drug: Placebo
* Drug: Cocaine IV
* Drug: Saline IV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: non-treatment-seeking cocaine users with a positive urine toxicology screen for cocaine at least once during screening have a medical history and physical examination that demonstrate no clinically significant contraindication for participating in the study males must use contraception; females must be of non-childbearing potential Exclusion Criteria: drug allergies or reactions to metyrapone or benzodiazepines, or severe hypersensitivity reactions (like angioedema) to any drugs history of clinically significant adverse reaction to cocaine a low out-of-range serum cortisol value at screening or subjects who have a heightened likelihood of having adrenal insufficiency, or have signs or a history of adrenal insufficiency or confounders of the levels of cortisol and/or cortisol binding globulin treatment with glucocorticoids history of seizures, benzodiazepine use disorder, respiratory disease, neurologic or neuromuscular disease, liver disease or cardiovascular disease other psychiatric or substance use disorders of clinical significance, or suicidality clinically significant finding on medical history, physical examination, clinical laboratory tests, vital signs or ECGs use of any other drugs abnormal BP or HR positive urine drug screen at for alcohol or any drug other than marijuana (THC) or cocaine positive serology test results for HIV-1/HIV-2 Antibodies, Hepatitis B surface Antigen (HBsAg) or Hepatitis C Antibody (HCVAb)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 55 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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMB-001 (oral)<br>EMB-001 will be orally administered for 7 consecutive days, twice daily for 6 days followed on the last day by one EMB-001 oral dose (QD) in the morning. Three hours later Cocaine IV or Saline IV will be administered followed 2 hours by the other (saline or cocaine). | Drug: EMB-001<br>* EMB-001 is a combination of metyrapone (720mg per dose in this study) and oxazepam (24mg per dose in this study)<br>* Other names: metyrapone and oxazepam;Drug: Cocaine IV<br>* Cocaine administered at doses of 20 and 40mg<br>* Other names: IV cocaine;Drug: Saline IV<br>* Cocaine matched placebo<br>* Other names: IV saline;|
| Placebo Comparator: Placebo (oral)<br>PLB-to-match EMB-001 will be orally administered for 7 consecutive days, BID for 6 days, followed on the last day by one PLB oral dose in the morning. Three hours later Cocaine IV or Saline IV will be administered followed 2 hours by the other (saline or cocaine). | Drug: Placebo<br>* EMB-001 matched placebo<br>* Other names: oral placebo;Drug: Cocaine IV<br>* Cocaine administered at doses of 20 and 40mg<br>* Other names: IV cocaine;Drug: Saline IV<br>* Cocaine matched placebo<br>* Other names: IV saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse event data (including clinically significant changes in laboratory values) will be compiled for EMB-001 and placebo cohorts. | 29 Days | 
| Vital signs | Blood Pressure (BP) and heart rate (HR) measures during saline infusions will be compared to HR and BP after cocaine infusion (40 mg). Changes in BP and HR induced by cocaine infusion along with EMB-001 will be compared to those with EMB-001-matched placebo. | 29 days | 
| ECGs | Changes in ECG readings during saline infusion will be compared to those taken during cocaine infusion along with EMB-001 will be compared to those with EMB-001-matched placebo. | 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter EMB-001 | Cmax (maximum concentration) of EMB-001 will be compared when taken alone and when taken with cocaine | 21 days | 
| PK Parameter Cocaine | Cmax (maximum concentration) of cocaine will be compared when taken alone and when taken with EMB-001 | 21 days | 
| PK Parameter EMB-001 | AUC (area under the curve) of EMB-001 will be compared when taken alone and when taken with cocaine | 21 days | 
| PK Parameter Cocaine | AUC (area under the curve) of Cocaine will be compared when taken alone and when taken with EMB-001 | 21 days |