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

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

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.

Study Overview

• Status: Completed
• Conditions: Cocaine Use Disorder
• Intervention / Treatment: Drug: EMB-001; Drug: Cocaine IV; Drug: Saline IV; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince & Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: metyrapone and oxazepam; Drug: Cocaine IV; Cocaine administered at doses of 20 and 40mg; Other Names: IV cocaine; Drug: Saline IV; Cocaine matched placebo; Other Names: 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: Cocaine IV; Cocaine administered at doses of 20 and 40mg; Other Names: IV cocaine; Drug: Saline IV; Cocaine matched placebo; Other Names: IV saline; Drug: Placebo; EMB-001 matched placebo; Other Names: oral placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Embera NeuroTherapeutics, Inc.
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Debra Kelsh, MD, Vince & Associates

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (ACTUAL): February 17, 2017
• Study Completion (ACTUAL): July 25, 2017

Study Registration Dates

• First Submitted: July 22, 2016
• First Submitted That Met QC Criteria: August 2, 2016
• First Posted (ESTIMATE): August 5, 2016

Study Record Updates

• Last Update Posted (ACTUAL): August 1, 2017
• Last Update Submitted That Met QC Criteria: July 31, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Antimetabolites; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Hypnotics and Sedatives; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Anesthetics, Local; Dopamine Uptake Inhibitors; Vasoconstrictor Agents; Metyrapone; Cocaine; Oxazepam
• Other Study ID Numbers: ERL-002; U01DA038879 (NIH)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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).
• IPD Sharing Time Frame: Every three months- blinded results
• IPD Sharing Access Criteria: A DSMB report is prepared an submitted via NIDA.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; CSR