Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Drug Users

A Single-Center, Single-Dose, Double-Blind, Double-Dummy, Placebo-Controlled, Randomized Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Users of Perception-Altering Drugs

The primary objective of this study is to evaluate the abuse potential of intranasal esketamine (112 milligram and 84 mg) compared to racemic intravenous ketamine (0.5 mg/kg) in nondependent, recreational polydrug users of perception-altering drugs.

Study Overview

• Status: Completed
• Conditions: Drug Abuse
• Intervention / Treatment: Drug: Intravenous placebo; Drug: Intranasal placebo; Drug: Intravenous racemic ketamine; Drug: Esketamine 112 mg; Drug: Esketamine 84 mg

Detailed Description

This is a single-center, single-dose, double-blind, double-dummy, placebo-controlled (participants are randomly assigned to a test treatment or to an identical-appearing treatment that does not contain the test drug), randomized (study medication assigned to participants by chance), crossover study in up to 120 men and women self-identifying as current, recreational, nondependent polydrug users. The study has a Screening Phase (consisting of a Screening Visit and a Qualification Session) and a Treatment Phase. In the Qualification Session participants will be randomized to receive Sequence 1: intravenous placebo and intranasal placebo concurrently (Treatment A) on Day 1 and an intravenous dose (0.5 mg/kg) of racemic ketamine and intranasal placebo concurrently (Treatment B) on Day 2, or the participants will receive Sequence 2: Treatment B on Day 1 and Treatment A on Day 2. In the Treatment Phase eligible participants will be administered 4 treatments: A, B, C (intravenous placebo and intranasal 84 mg esketamine as 3 devices, each with 28 mg esketamine followed by 1 device with placebo) and D (intravenous placebo and intranasal 112 mg of esketamine as 4 devices, each with 28 mg esketamine) in a cross-over manner (1 treatment per period) in Sequence 3, 4, 5, or 6. Periods 1, 2, 3, and 4 will be separated by 7 to 14 days. Primarily the drug abuse potential will be evaluated. Safety of the participants will be monitored throughout the study.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants with body mass index (BMI) between 18 and 30 kilogram per square meter (kg/m^2) (inclusive), and body weight not less than 50 kg
• Signed an informed consent document indicating they understand the purpose of and procedures required for the study and are willing to participate in the study, including the pharmacogenomic research component of the study
• Be a current, recreational, nondependent, polydrug user defined as nonmedical use with at least 2 types of perception-altering drugs of abuse (example, lysergic acid diethylamide, cannabinoids, ketamine, ecstasy/3,4-methylenedioxy-methamphetamine, phencyclidine, psilocybin, and ring-substituted amphetamines with perception altering effects) and at least 10 total lifetime occasions of use with perception-altering drugs of abuse and who like their effects
• Report having used ketamine at least once in a lifetime without moderate or severe adverse effects
• Report having used a perception-altering drug (example, lysergic acid diethylamide, cannabinoids, ketamine, ecstasy/3,4-methylenedioxy-methamphetamine, phencyclidine, psilocybin, and ring substituted amphetamines with perception altering effects) at least once within 3 months prior to the screening phase without moderate or severe adverse effects

Exclusion Criteria:

• Participant with a history of or current clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, hepatic or renal insufficiency, thyroid disease, neurologic disease, infection, hypertension or vascular disorder, kidney or urinary tract disturbances, sleep apnea, myasthenia gravis, or any other illness that the investigator considers should exclude the participant or that could interfere with the interpretation of the study results
• Participant has a current or prior diagnosis of psychotic or bipolar disorder
• Participant with clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at screening or at admission to the study center (Day -1 of the Qualification Session and each period of the Treatment Phase) as determined by the investigator
• Participant with a history or presence of drug (excluding nicotine or caffeine) or alcohol dependence according to the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria
• Participation in treatment for substance-related disorders within 3 years prior to Screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence 1: Qualification Session; Participants will receive Treatment A (intravenous placebo and intranasal placebo concurrently) on Day 1 and Treatment B (0.5 milligram per kilogram (mg/kg) of intravenous racemic ketamine and intranasal placebo concurrently) on Day 2.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.
Experimental: Sequence 2: Qualification Session; Participants will receive Treatment B (0.5 mg/kg of intravenous racemic ketamine and intranasal placebo concurrently) on Day 1 and Treatment A (intravenous placebo and intranasal placebo concurrently) on Day 2.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.
Experimental: Sequence 3: Treatment Phase; Participants in Sequence 3 will receive Treatment A (intravenous placebo and intranasal placebo) on Day 1 of period 1, Treatment D (intravenous placebo and intranasal 112 milligram (mg) of esketamine as 4 devices, each with 28 mg esketamine) on Day 1 of period 2, Treatment B (0.5 mg/kg of intravenous racemic ketamine and intranasal placebo) on Day 1 of period 3, Treatment C (intravenous placebo and intranasal 84 mg esketamine as 3 devices, each with 28 mg esketamine followed by 1 device with placebo) on Day 1 of period 4. Periods 1, 2, 3 and 4 will be separated by 7 to 14 days.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.; Drug: Esketamine 112 mg; Participants will receive 112 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 6, on Day 1 of Period 2 in Sequence 3, on Day 1 of Period 3 in Sequence 5, and on Day 1 of Period 4 in Sequence 4.; Drug: Esketamine 84 mg; Participants will receive 84 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 5, on Day 1 of Period 2 in Sequence 6, on Day 1 of Period 3 in Sequence 4, and on Day 1 of Period 4 in Sequence 3.
Experimental: Sequence 4: Treatment Phase; Participants in Sequence 4 will receive Treatment B on Day 1 of period 1, Treatment A on Day 1 of period 2, Treatment C on Day 1 of period 3, Treatment D on Day 1 of period 4. Periods 1, 2, 3 and 4 will be separated by 7 to 14 days.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.; Drug: Esketamine 112 mg; Participants will receive 112 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 6, on Day 1 of Period 2 in Sequence 3, on Day 1 of Period 3 in Sequence 5, and on Day 1 of Period 4 in Sequence 4.; Drug: Esketamine 84 mg; Participants will receive 84 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 5, on Day 1 of Period 2 in Sequence 6, on Day 1 of Period 3 in Sequence 4, and on Day 1 of Period 4 in Sequence 3.
Experimental: Sequence 5: Treatment Phase; Participants in Sequence 5 will receive Treatment C on Day 1 of period 1, Treatment B on Day 1 of period 2, Treatment D on Day 1 of period 3, Treatment A on Day 1 of period 4. Periods 1, 2, 3 and 4 will be separated by 7 to 14 days.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.; Drug: Esketamine 112 mg; Participants will receive 112 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 6, on Day 1 of Period 2 in Sequence 3, on Day 1 of Period 3 in Sequence 5, and on Day 1 of Period 4 in Sequence 4.; Drug: Esketamine 84 mg; Participants will receive 84 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 5, on Day 1 of Period 2 in Sequence 6, on Day 1 of Period 3 in Sequence 4, and on Day 1 of Period 4 in Sequence 3.
Experimental: Sequence 6: Treatment Phase; Participants in Sequence 6 will receive Treatment D on Day 1 of period 1, Treatment C on Day 1 of period 2, Treatment A on Day 1 of period 3, Treatment B on Day 1 of period 4. Periods 1, 2, 3 and 4 will be separated by 7 to 14 days.	Drug: Intravenous placebo; Participants will receive placebo, 40-minute, intravenous infusion on Day 1 of Sequence 1, on Day 2 of Sequence 2, on Day 1 of Period 1 in Sequence 3, 5 and 6, on Day 1 of Period 2 in Sequence 3, 4 and 6, on Day 1 of Period 3 in Sequence 4, 5 and 6, and on Day 1 of Period 4 in Sequence 3, 4 and 5.; Drug: Intranasal placebo; Participants will receive placebo, intranasally, on Day 1 or Day 2 in Sequence 1 and 2, on Day 1 of Period 1 in Sequence 3 and 4, on Day 1 of Period 2 in Sequence 4 and 5, on Day 1 of Period 3 in Sequence 3 and 6 and on Day 1 of Period 4 in Sequence 5 and 6.; Drug: Intravenous racemic ketamine; Participants will receive 0.5 mg/kg racemic ketamine, intranasally, on Day 2 in sequence 1, on Day 1 in sequence 2, on Day 1 of Period 1 in Sequence 4, on Day 1 of Period 2 in Sequence 5, on Day 1 of Period 3 in Sequence 3, and on Day 1 of Period 4 in Sequence 6.; Drug: Esketamine 112 mg; Participants will receive 112 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 6, on Day 1 of Period 2 in Sequence 3, on Day 1 of Period 3 in Sequence 5, and on Day 1 of Period 4 in Sequence 4.; Drug: Esketamine 84 mg; Participants will receive 84 mg of Esketamine, intranasally, on Day 1 of Period 1 in Sequence 5, on Day 1 of Period 2 in Sequence 6, on Day 1 of Period 3 in Sequence 4, and on Day 1 of Period 4 in Sequence 3.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in abuse potential based on Visual Analog Scale	The abuse potential will be assessed based on visual analog scale (VAS). The VAS score will include for Balancing Measures, Positive and Negative effect at the moment, Perceptual / Dissociative Effects and others).	up to Day 2 Period 4 in Treatment Phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Clinician-Administered Dissociative States Scale (CADSS) Score	The CADSS is a clinician administered rating scale designed to measure dissociative symptoms. The CADSS comprises 23 subjective items, divided into 3 components: depersonalization, derealization and amnesia. Participant's responses are coded on a 5-point scale (0 = "Not at all" through to 4 = "Extremely). Higher scores indicate worsening	up to Day 2 Period 4 in Treatment Phase
Change From Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) Score	The C-SSRS is a clinical interview to assess severity and track suicidal events providing a summary of both suicidal ideation and behavior to identify the level and type of suicidality present.	up to Day 2 Period 4 in Treatment Phase
Percentage of Participants with Serious Adverse Events (SAEs) and Adverse Events (AEs)		Screening to follow-up visit (11 to 13 days after last dose of study medication)
Maximum Observed Plasma Concentration (Cmax)	Cmax is defined as maximum observed analyte concentration.	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Time to Reach Maximum Observed Plasma Concentration (Tmax)	Tmax is defined as actual sampling time to reach maximum observed analyte concentration.	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to Time at Last Observed Quantifiable Concentration (AUClast)	The AUClast is area under the plasma concentration-time curve from time zero to the last quantifiable concentration.	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])	The AUC(0-infinity) is area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of Area under Curve (AUC) last and C(last)/lambda(z), in which C(last) is the last observed quantifiable concentration	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Area Under the Plasma Concentration-Time Curve From Time Zero to 12 Hours (AUC [0-12])	The AUC (0-12) is the area under the plasma concentration-time curve from time 0 to 12 hours post-dose.	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Elimination Half-Life Period (T1/2)	T1/2 is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal rate-constant (lambda[z]) of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
First-order Rate Constant	First-order rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Total Body Clearance (CLT/F)	Total body clearance will be calculated as dose/AUC(INF). AUC(INF) will be estimated as AUC(0-T) + Ct/λ z, where λ z is the terminal elimination rate constant and Ct is the last observable concentration	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Volume of Distribution (Vd/F)	The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].	Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Cmax Metabolite to Parent Ratio (MPR Cmax)		Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
AUC(last) Metabolite to Parent Ratio (MPR AUC[last])		Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity])		Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours post-dose on Day 1
Change from baseline in Nasal Tolerability Questionnaire	Participants need to complete a nasal tolerability questionnaire from Screening to end of the study. The questionnaire will be containing different type symptoms with rating (None, mild, moderate and severe).	up to Day 2 in Period 4 of Treatment Phase

Collaborators and Investigators

• Sponsor: Janssen Research & Development, LLC

Publications and helpful links

General Publications

• Perez-Ruixo C, Rossenu S, Zannikos P, Nandy P, Singh J, Drevets WC, Perez-Ruixo JJ. Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clin Pharmacokinet. 2021 Apr;60(4):501-516. doi: 10.1007/s40262-020-00953-4. Epub 2020 Oct 31.

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2016
• Primary Completion (Actual): January 9, 2017
• Study Completion (Actual): January 9, 2017

Study Registration Dates

• First Submitted: February 10, 2016
• First Submitted That Met QC Criteria: February 10, 2016
• First Posted (Estimate): February 15, 2016

Study Record Updates

• Last Update Posted (Actual): March 16, 2017
• Last Update Submitted That Met QC Criteria: March 14, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Placebo; Esketamine; Racemic ketamine
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Psychotropic Drugs; Antidepressive Agents; Ketamine; Esketamine
• Other Study ID Numbers: CR108104; 54135419TRD1015 (Other Identifier: Janssen Research & Development, LLC)