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

Primary Purpose

Drug Abuse

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Intravenous placebo

Intranasal placebo

Intravenous racemic ketamine

Esketamine 112 mg

Esketamine 84 mg

About this trial

This is an interventional treatment trial for Drug Abuse focused on measuring Esketamine, Placebo, Racemic ketamine, Pharmacokinetics

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Arm Label

Sequence 1: Qualification Session

Sequence 2: Qualification Session

Sequence 3: Treatment Phase

Sequence 4: Treatment Phase

Sequence 5: Treatment Phase

Sequence 6: Treatment Phase

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

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.

Percentage of Participants with Serious Adverse Events (SAEs) and Adverse Events (AEs)

Maximum Observed Plasma Concentration (Cmax)

Cmax is defined as maximum observed analyte concentration.

Time to Reach Maximum Observed Plasma Concentration (Tmax)

Tmax is defined as actual sampling time to reach maximum observed analyte concentration.

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.

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

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.

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).

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.

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

Volume of Distribution (Vd/F)

The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].

Cmax Metabolite to Parent Ratio (MPR Cmax)

AUC(last) Metabolite to Parent Ratio (MPR AUC[last])

AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity])

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).

Full Information

NCT ID

NCT02682225

First Posted

February 10, 2016

Last Updated

March 14, 2017

Sponsor

Janssen Research & Development, LLC

1. Study Identification

Unique Protocol Identification Number

NCT02682225

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

March 25, 2016 (Actual)

Primary Completion Date

January 9, 2017 (Actual)

Study Completion Date

January 9, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Drug Abuse

Keywords

Esketamine, Placebo, Racemic ketamine, Pharmacokinetics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

55 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sequence 1: Qualification Session

Arm Type

Experimental

Arm Description

Arm Title

Sequence 2: Qualification Session

Arm Type

Experimental

Arm Description

Arm Title

Sequence 3: Treatment Phase

Arm Type

Experimental

Arm Description

Arm Title

Sequence 4: Treatment Phase

Arm Type

Experimental

Arm Description

Arm Title

Sequence 5: Treatment Phase

Arm Type

Experimental

Arm Description

Arm Title

Sequence 6: Treatment Phase

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Intravenous placebo

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Intranasal placebo

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Intravenous racemic ketamine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Esketamine 112 mg

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Esketamine 84 mg

Intervention Description

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.

Primary Outcome Measure Information:

Title

Change From Baseline in abuse potential based on Visual Analog Scale

Description

Time Frame

up to Day 2 Period 4 in Treatment Phase

Secondary Outcome Measure Information:

Title

Change From Baseline in Clinician-Administered Dissociative States Scale (CADSS) Score

Description

Time Frame

up to Day 2 Period 4 in Treatment Phase

Title

Change From Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) Score

Description

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.

Time Frame

up to Day 2 Period 4 in Treatment Phase

Title

Percentage of Participants with Serious Adverse Events (SAEs) and Adverse Events (AEs)

Time Frame

Screening to follow-up visit (11 to 13 days after last dose of study medication)

Title

Maximum Observed Plasma Concentration (Cmax)

Description

Cmax is defined as maximum observed analyte concentration.

Time Frame