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

Primary Purpose

Hepatic Impairment, Normal Hepatic Function

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Esketamine
Sponsored by
Janssen Research & Development, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatic Impairment focused on measuring Healthy, Esketamine, Hepatic Impairment, Pharmacokinetics

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Maximum Plasma Concentration (Cmax)
The Cmax is the maximum plasma concentration.
Time to Reach Maximum Concentration (tmax)
Time to reach the maximum observed plasma concentration.
Area Under the Plasma Concentration-Time Curve From Time Zero to Last (AUC [0-last])
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.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])
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.
Elimination Half-life period (t1/2) Associated with the Terminal Slope (Lambda z)
Elimination half-life associated with the terminal slope (lambda[z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).
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.
Rate Constant (Lambda[z])
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.
Cmax Metabolite to Parent Ratio (MPR Cmax)
Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.
AUC(last) Metabolite to Parent Ratio (MPR AUC[last])
AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.
AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity])
AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.
Amount of Drug Excreted in Urine (Ae)
Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.
Percentage of Drug dose Excreted into Urine
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.
Renal Clearance
Renal clearance calculated as Ae/AUC (infinity).
Ae Metabolite to Parent Ratio (MPR Ae)
Ae metabolite to parent ratio, and corrected for molecular weight if necessary.

Secondary Outcome Measures

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.

Full Information

First Posted
November 19, 2015
Last Updated
May 12, 2017
Sponsor
Janssen Research & Development, LLC
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1. Study Identification

Unique Protocol Identification Number
NCT02611505
Brief Title
A Study to Assess the Effects of Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of Intranasally Administered Esketamine
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
November 30, 2015 (Actual)
Primary Completion Date
February 27, 2017 (Actual)
Study Completion Date
February 27, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatic Impairment, Normal Hepatic Function
Keywords
Healthy, Esketamine, Hepatic Impairment, Pharmacokinetics

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Esketamine
Other Intervention Name(s)
JNJ-54135419
Intervention Description
Esketamine 28 mg will be self-administered by participants as intranasal spray at 0 hour (h) on Day 1.
Primary Outcome Measure Information:
Title
Maximum Plasma Concentration (Cmax)
Description
The Cmax is the maximum plasma concentration.
Time Frame
up to 60 hours after study drug administration
Title
Time to Reach Maximum Concentration (tmax)
Description
Time to reach the maximum observed plasma concentration.
Time Frame
up to 60 hours after study drug administration
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to Last (AUC [0-last])
Description
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.
Time Frame
up to 60 hours after study drug administration
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity])
Description
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.
Time Frame
up to 60 hours after study drug administration
Title
Elimination Half-life period (t1/2) Associated with the Terminal Slope (Lambda z)
Description
Elimination half-life associated with the terminal slope (lambda[z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).
Time Frame
up to 60 hours after study drug administration
Title
Area Under the Plasma Concentration-Time Curve From Time Zero to 12 Hours (AUC [0-12])
Description
The AUC (0-12) is the area under the plasma concentration-time curve from time 0 to 12 hours post-dose.
Time Frame
up to 12 hours after study drug administration
Title
Rate Constant (Lambda[z])
Description
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.
Time Frame
up to 60 hours after study drug administration
Title
Cmax Metabolite to Parent Ratio (MPR Cmax)
Description
Cmax metabolite to parent ratio, and corrected for molecular weight if necessary.
Time Frame
up to 60 hours after study drug administration
Title
AUC(last) Metabolite to Parent Ratio (MPR AUC[last])
Description
AUC(last) metabolite to parent ratio, and corrected for molecular weight if necessary.
Time Frame
up to 60 hours after study drug administration
Title
AUC (infinity) Metabolite to Parent Ratio (MPR AUC [infinity])
Description
AUC (infinity) metabolite to parent ratio, and corrected for molecular weight if necessary.
Time Frame
up to 60 hours after study drug administration
Title
Amount of Drug Excreted in Urine (Ae)
Description
Total amount excreted into the urine, calculated as the sum of all Ae(t1-t2) intervals.
Time Frame
up to 60 hours after study drug administration
Title
Percentage of Drug dose Excreted into Urine
Description
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.
Time Frame
up to 60 hours after study drug administration
Title
Renal Clearance
Description
Renal clearance calculated as Ae/AUC (infinity).
Time Frame
up to 60 hours after study drug administration
Title
Ae Metabolite to Parent Ratio (MPR Ae)
Description
Ae metabolite to parent ratio, and corrected for molecular weight if necessary.
Time Frame
up to 60 hours after study drug administration
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Baseline up to Day 11

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Janssen Research & Development, LLC Clinical Trial
Organizational Affiliation
Janssen Research & Development, LLC
Official's Role
Study Director
Facility Information:
City
Knoxville
State/Province
Tennessee
Country
United States

12. IPD Sharing Statement

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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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