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

• ClinicalTrials.gov Identifier: NCT02856854
• Recruitment Status: Completed
• First Posted: August 5, 2016
• Last Update Posted: August 1, 2017
• Sponsor: Embera NeuroTherapeutics, Inc.
• Collaborator: National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): Embera NeuroTherapeutics, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cocaine Use Disorder	Drug: EMB-001; Drug: Placebo; Drug: Cocaine IV; Drug: Saline IV	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: July 2016
• Actual Primary Completion Date: February 17, 2017
• Actual Study Completion Date: July 25, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: EMB-001 (oral); 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; EMB-001 is a combination of metyrapone (720mg per dose in this study) and oxazepam (24mg per dose in this study); Other Name: metyrapone and oxazepam; Drug: Cocaine IV; Cocaine administered at doses of 20 and 40mg; Other Name: IV cocaine; Drug: Saline IV; Cocaine matched placebo; Other Name: IV saline
Placebo Comparator: Placebo (oral); 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; EMB-001 matched placebo; Other Name: oral placebo; Drug: Cocaine IV; Cocaine administered at doses of 20 and 40mg; Other Name: IV cocaine; Drug: Saline IV; Cocaine matched placebo; Other Name: IV saline

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 29 Days ]
   Adverse event data (including clinically significant changes in laboratory values) will be compiled for EMB-001 and placebo cohorts.
2. Vital signs [ Time Frame: 29 days ]
   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.
3. ECGs [ Time Frame: 29 days ]
   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.

Secondary Outcome Measures :

1. PK Parameter EMB-001 [ Time Frame: 21 days ]
   Cmax (maximum concentration) of EMB-001 will be compared when taken alone and when taken with cocaine
2. PK Parameter Cocaine [ Time Frame: 21 days ]
   Cmax (maximum concentration) of cocaine will be compared when taken alone and when taken with EMB-001
3. PK Parameter EMB-001 [ Time Frame: 21 days ]
   AUC (area under the curve) of EMB-001 will be compared when taken alone and when taken with cocaine
4. PK Parameter Cocaine [ Time Frame: 21 days ]
   AUC (area under the curve) of Cocaine will be compared when taken alone and when taken with EMB-001

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, Kansas

Vince & Associates

Overland Park, Kansas, United States, 66212

Sponsors and Collaborators

Embera NeuroTherapeutics, Inc.

National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Debra Kelsh, MD; Vince & Associates

More Information

Publications:

Kablinger AS, Lindner MA, Casso S, Hefti F, DeMuth G, Fox BS, McNair LA, McCarthy BG, Goeders NE. Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study. J Psychopharmacol. 2012 Jul;26(7):973-81. doi: 10.1177/0269881111430745. Epub 2012 Jan 11.

• Responsible Party: Embera NeuroTherapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT02856854
• Other Study ID Numbers: ERL-002; U01DA038879 ( U.S. NIH Grant/Contract )
• First Posted: August 5, 2016
• Last Update Posted: August 1, 2017
• Last Verified: July 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Every three months, the NIDA DSMB will convene to review the overall safety data, as well as data on safety summarized by treatment condition. As per NIH guidelines, the objective of these reviews will be to determine whether continued conduct of the trial poses any undue risk for participants. Blinded data tables, figures and/or listings will be provided to the Data Safety Monitoring Board (DSMB).
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• Time Frame: Every three months- blinded results
• Access Criteria: A DSMB report is prepared an submitted via NIDA.

Additional relevant MeSH terms:

Cocaine; Oxazepam; Metyrapone; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Vasoconstrictor Agents; Dopamine Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Dopamine Agents; Neurotransmitter Agents; Antimetabolites; Enzyme Inhibitors; Hypnotics and Sedatives; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; GABA Modulators; GABA Agents