Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Drug Users
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ClinicalTrials.gov Identifier: NCT02682225 
Recruitment Status
:
Completed
First Posted
: February 15, 2016
Last Update Posted
: March 16, 2017

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Condition or disease  Intervention/treatment  Phase 

Drug Abuse  Drug: Intravenous placebo Drug: Intranasal placebo Drug: Intravenous racemic ketamine Drug: Esketamine 112 mg Drug: Esketamine 84 mg  Phase 1 
Study Type :  Interventional (Clinical Trial) 
Actual Enrollment :  55 participants 
Allocation:  Randomized 
Intervention Model:  Crossover Assignment 
Masking:  Double (Participant, Investigator) 
Primary Purpose:  Treatment 
Official Title:  A SingleCenter, SingleDose, DoubleBlind, DoubleDummy, PlaceboControlled, Randomized Crossover Study to Evaluate the Abuse Potential of Intranasal Esketamine Compared to Racemic Intravenous Ketamine in Nondependent, Recreational Users of PerceptionAltering Drugs 
Actual Study Start Date :  March 25, 2016 
Primary Completion Date :  January 9, 2017 
Study Completion Date :  January 9, 2017 
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, 40minute, 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, 40minute, 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, 40minute, 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, 40minute, 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, 40minute, 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, 40minute, 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.

 Change From Baseline in abuse potential based on Visual Analog Scale [ Time Frame: up to Day 2 Period 4 in Treatment Phase ]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).
 Change From Baseline in ClinicianAdministered Dissociative States Scale (CADSS) Score [ Time Frame: up to Day 2 Period 4 in Treatment Phase ]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 5point scale (0 = "Not at all" through to 4 = "Extremely). Higher scores indicate worsening
 Change From Baseline in Columbia Suicide Severity Rating Scale (CSSRS) Score [ Time Frame: up to Day 2 Period 4 in Treatment Phase ]The CSSRS 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) [ Time Frame: Screening to followup visit (11 to 13 days after last dose of study medication) ]
 Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]Cmax is defined as maximum observed analyte concentration.
 Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
 Area Under the Plasma ConcentrationTime Curve From Time Zero to Time at Last Observed Quantifiable Concentration (AUClast) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]The AUClast is area under the plasma concentrationtime curve from time zero to the last quantifiable concentration.
 Area Under the Plasma ConcentrationTime Curve From Time Zero to Infinite Time (AUC [0infinity]) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]The AUC(0infinity) is area under the plasma concentrationtime 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 ConcentrationTime Curve From Time Zero to 12 Hours (AUC [012]) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]The AUC (012) is the area under the plasma concentrationtime curve from time 0 to 12 hours postdose.
 Elimination HalfLife Period (T1/2) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]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 rateconstant (lambda[z]) of the semi logarithmic drug concentrationtime curve, and is calculated as 0.693/lambda(z).
 Firstorder Rate Constant [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]Firstorder rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal loglinear phase of the drug concentrationtime curve.
 Total Body Clearance (CLT/F) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]Total body clearance will be calculated as dose/AUC(INF). AUC(INF) will be estimated as AUC(0T) + Ct/λ z, where λ z is the terminal elimination rate constant and Ct is the last observable concentration
 Volume of Distribution (Vd/F) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]The Vd/F is defined as Dose/[Lambda (z)*AUC (0infinity)].
 Cmax Metabolite to Parent Ratio (MPR Cmax) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]
 AUC(last) Metabolite to Parent Ratio (MPR AUC[last]) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]
 AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity]) [ Time Frame: Predose, 0.17, 0.33, 0.5, 0.67, 1, 1.5, 2, 2.5, 3, 4, 8, 12, and 24 hours postdose on Day 1 ]
 Change from baseline in Nasal Tolerability Questionnaire [ Time Frame: up to Day 2 in Period 4 of Treatment Phase ]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).
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Ages Eligible for Study:  18 Years to 55 Years (Adult) 
Sexes Eligible for Study:  All 
Accepts Healthy Volunteers:  Yes 
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 perceptionaltering drugs of abuse (example, lysergic acid diethylamide, cannabinoids, ketamine, ecstasy/3,4methylenedioxymethamphetamine, phencyclidine, psilocybin, and ringsubstituted amphetamines with perception altering effects) and at least 10 total lifetime occasions of use with perceptionaltering 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 perceptionaltering drug (example, lysergic acid diethylamide, cannabinoids, ketamine, ecstasy/3,4methylenedioxymethamphetamine, 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 (DSMIV) criteria
 Participation in treatment for substancerelated disorders within 3 years prior to Screening
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02682225
United States, Utah  
Salt Lake City, Utah, United States 
Study Director:  Janssen Research & Development, LLC Clinical Trial  Janssen Research & Development, LLC 
Responsible Party:  Janssen Research & Development, LLC 
ClinicalTrials.gov Identifier:  NCT02682225 History of Changes 
Other Study ID Numbers: 
CR108104 54135419TRD1015 ( Other Identifier: Janssen Research & Development, LLC ) 
First Posted:  February 15, 2016 Key Record Dates 
Last Update Posted:  March 16, 2017 
Last Verified:  March 2017 
Keywords provided by Janssen Research & Development, LLC:
Esketamine Placebo Racemic ketamine Pharmacokinetics 
Additional relevant MeSH terms:
SubstanceRelated Disorders ChemicallyInduced Disorders Mental Disorders Ketamine Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anesthetics, Dissociative 
Anesthetics, Intravenous Anesthetics, General Anesthetics Central Nervous System Depressants Excitatory Amino Acid Antagonists Excitatory Amino Acid Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action 