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

• ClinicalTrials.gov Identifier: NCT02682225
• Recruitment Status: Completed
• First Posted: February 15, 2016
• Last Update Posted: March 16, 2017
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Tracking Information

• First Submitted Date: February 10, 2016
• First Posted Date: February 15, 2016
• Last Update Posted Date: March 16, 2017
• Actual Study Start Date: March 25, 2016
• Actual Primary Completion Date: January 9, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 10, 2016)

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 10, 2016)

• Change From Baseline in Clinician-Administered 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 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 [ Time Frame: up to Day 2 Period 4 in Treatment Phase ]
  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) [ Time Frame: Screening to follow-up 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 post-dose 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 post-dose on Day 1 ]
  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) [ Time Frame: 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 ]
  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]) [ Time Frame: 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 ]
  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]) [ Time Frame: 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 ]
  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) [ Time Frame: 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 ]
  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 [ Time Frame: 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 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) [ Time Frame: 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 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) [ Time Frame: 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 ]
  The Vd/F is defined as Dose/[Lambda (z)*AUC (0-infinity)].
• 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 post-dose 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 post-dose 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 post-dose 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).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Drug Abuse

Intervention

• 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.

Study Arms

• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
  • Drug: Esketamine 112 mg
  • Drug: Esketamine 84 mg
• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
  • Drug: Esketamine 112 mg
  • Drug: Esketamine 84 mg
• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
  • Drug: Esketamine 112 mg
  • Drug: Esketamine 84 mg
• 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.
  Interventions:

  • Drug: Intravenous placebo
  • Drug: Intranasal placebo
  • Drug: Intravenous racemic ketamine
  • Drug: Esketamine 112 mg
  • Drug: Esketamine 84 mg

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 14, 2017): 55
• Original Estimated Enrollment (submitted: February 10, 2016): 120
• Actual Study Completion Date: January 9, 2017
• Actual Primary Completion Date: January 9, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02682225
• Other Study ID Numbers: CR108104; 54135419TRD1015 ( Other Identifier: Janssen Research & Development, LLC )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Janssen Research & Development, LLC
• Study Sponsor: Janssen Research & Development, LLC
• Collaborators: Not Provided

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

• PRS Account: Janssen Research & Development, LLC
• Verification Date: March 2017