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A Study to Assess the Effects of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine

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ClinicalTrials.gov Identifier: NCT02611505
Recruitment Status : Completed
First Posted : November 20, 2015
Last Update Posted : May 15, 2017
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The purpose of this study is to evaluate the pharmacokinetics, safety, and tolerability of intranasally administered esketamine in both participants with varying stages of hepatic impairment and healthy participants.

Condition or disease Intervention/treatment Phase
Hepatic Impairment Normal Hepatic Function Drug: Esketamine Phase 1

Detailed Description:
This is a parallel group, single-center, single-dose, open-label (all people know the identity of the intervention), study to assess the pharmacokinetics and safety of a single 28 milligram (mg) dose of esketamine in both participants with varying stages of hepatic impairment and healthy participants. The participants will be assigned to 1 of 3 groups (8 participants per group) based on hepatic impairment which will be classified during Screening. Cohort 1 (participants with moderate hepatic impairment), Cohort 2 (participants with mild hepatic impairment), and Cohort 3 (participants with normal hepatic function and no evidence of liver damage). Participants will self-administer a single dose of intranasal Esketamine 28 mg. The total duration of the study from Screening through Follow-up, is approximately 34 to 38 days. Blood and urine samples for assessment of Esketamine pharmacokinetics will be collected for up to 60 hours after study drug administration. Participants' safety will be monitored throughout the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Single-Dose, Parallel-Group Study to Assess the Effects of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine
Actual Study Start Date : November 30, 2015
Actual Primary Completion Date : February 27, 2017
Actual Study Completion Date : February 27, 2017

Arm Intervention/treatment
Experimental: Cohort 1
Participants with moderate hepatic impairment will receive esketamine solution (containing 14 milligram [mg] of esketamine base per 100 microliter [mcl]) by intranasal route into each nostril using nasal spray pump at 0 hour (h) on Day 1.
Drug: Esketamine
Esketamine 28 mg will be self-administered by participants as intranasal spray at 0 hour (h) on Day 1.
Other Name: JNJ-54135419

Experimental: Cohort 2
Participants with mild hepatic impairment will receive esketamine solution (containing 14 mg of esketamine base per 100 mcl) by intranasal route into each nostril using nasal spray pump at 0h on Day 1.
Drug: Esketamine
Esketamine 28 mg will be self-administered by participants as intranasal spray at 0 hour (h) on Day 1.
Other Name: JNJ-54135419

Experimental: Cohort 3
Participants with normal hepatic function and no evidence of liver damage will receive esketamine solution (containing 14 mg of esketamine base per 100 mcl) by intranasal route into each nostril using nasal spray pump at 0h on Day 1.
Drug: Esketamine
Esketamine 28 mg will be self-administered by participants as intranasal spray at 0 hour (h) on Day 1.
Other Name: JNJ-54135419




Primary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) [ Time Frame: up to 60 hours after study drug administration ]
    The Cmax is the maximum plasma concentration.

  2. Time to Reach Maximum Concentration (tmax) [ Time Frame: up to 60 hours after study drug administration ]
    Time to reach the maximum observed plasma concentration.

  3. Area Under the Plasma Concentration-Time Curve From Time Zero to Last (AUC [0-last]) [ Time Frame: up to 60 hours after study drug administration ]
    The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time, calculated as the sum of AUC(last) and C(last)/lambda(z), wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  4. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) [ Time Frame: up to 60 hours after study drug administration ]
    The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z), wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time; and C(last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  5. Elimination Half-life period (t1/2) Associated with the Terminal Slope (Lambda z) [ Time Frame: up to 60 hours after study drug administration ]
    Elimination half-life associated with the terminal slope (lambda[z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).

  6. Area Under the Plasma Concentration-Time Curve From Time Zero to 12 Hours (AUC [0-12]) [ Time Frame: up to 12 hours after study drug administration ]
    The AUC (0-12) is the area under the plasma concentration-time curve from time 0 to 12 hours post-dose.

  7. Rate Constant (Lambda[z]) [ Time Frame: up to 60 hours after study drug administration ]
    Lambda(z) is 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.

  8. Cmax Metabolite to Parent Ratio (MPR Cmax) [ Time Frame: up to 60 hours after study drug administration ]
    Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.

  9. AUC(last) Metabolite to Parent Ratio (MPR AUC[last]) [ Time Frame: up to 60 hours after study drug administration ]
    AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.

  10. AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity]) [ Time Frame: up to 60 hours after study drug administration ]
    AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.

  11. Amount of Drug Excreted in Urine (Ae) [ Time Frame: up to 60 hours after study drug administration ]
    Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.

  12. Percentage of Drug dose Excreted into Urine [ Time Frame: up to 60 hours after study drug administration ]
    Total amount excreted into the urine, expressed as a percentage of the administered dose, calculated as (Ae/dose)*100, and corrected for molecular weight if necessary.

  13. Renal Clearance [ Time Frame: up to 60 hours after study drug administration ]
    Renal clearance calculated as Ae/AUC (infinity).

  14. Ae Metabolite to Parent Ratio (MPR Ae) [ Time Frame: up to 60 hours after study drug administration ]
    Ae metabolite to parent ratio, and corrected for molecular weight if necessary.


Secondary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Day 11 ]
    An AE is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged in-patient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Cohorts 1, 2 and 3 (All participants):

  • Body mass index (BMI) between 18 and 34 kilogram (kg)/meter square ([m]^2) (inclusive), and body weight not less than 50 kilogram (kg)
  • Creatinine clearance of greater than or equal to (> =) 60 milliliter per minute (mL/min) based on the Cockcroft-Gault equation
  • 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

Cohorts 1 and 2 (Participants with Hepatic impairment):

  • A total Child-Pugh score of 5 or 6 for participants with mild impairment and between 7 and 9 (inclusive) for participants with moderate impairment
  • Participants must have stable hepatic function and consistent classification (mild or moderate hepatic impairment) between Screening and Day -1

Exclusion Criteria:

Cohorts 1, 2 and 3 (All participants):

  • Participants of Asian origin
  • Diagnosed with a current or previous psychotic or major depressive disorder (MDD) with psychosis, bipolar or related disorder, intellectual disability, borderline personality disorder, or antisocial personality disorder

Cohorts 1 and 2 (Participants with Hepatic impairment):

  • History of hepatopulmonary syndrome, hydrothorax or hepatorenal syndrome
  • Positive test for alcohol or drugs of abuse per local standard practices

Cohorts 3 (Healthy participants):

  • Clinically significant medical illness
  • Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at Screening or at admission to the study center (Day -1) as deemed appropriate by the investigator
  • Positive test for human immunodeficiency virus (HIV) 1 and 2 antibodies, hepatitis B surface antigen (HBsAg), or hepatitis C antibodies at Screening

Information from the National Library of Medicine

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): NCT02611505


Locations
United States, Tennessee
Knoxville, Tennessee, United States
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02611505     History of Changes
Other Study ID Numbers: CR108098
ESKETINTRD1011 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: November 20, 2015    Key Record Dates
Last Update Posted: May 15, 2017
Last Verified: May 2017

Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:
Healthy
Esketamine
Hepatic Impairment
Pharmacokinetics

Additional relevant MeSH terms:
Liver Diseases
Digestive System Diseases