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A Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Participants

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ClinicalTrials.gov Identifier: NCT02343289
Recruitment Status : Completed
First Posted : January 21, 2015
Last Update Posted : September 28, 2015
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Brief Summary:
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of esketamine administered by the intranasal (administered through the nose) and oral routes and to evaluate the effects of clarithromycin on the pharmacokinetics of intranasally administered esketamine.

Condition or disease Intervention/treatment Phase
Healthy Drug: Esketamine Drug: Clarithromycin Phase 1

Detailed Description:
This is a single-center, 4-period, fixed-sequence, open-label study. The study consists of Screening Period (Days -21 to -2), Open-label Treatment Period 1, 2, 3, 4 and End of Study (9 to 13 days after final dose or at Early Withdrawal). The total duration of study will be up to 98 days. For all 4 periods, the participants will be admitted into the study center on Day -1 of each treatment period and receive a 28 milligram (mg) (intravenous) or 84 mg (oral and intranasal) esketamine dose regimen on Day 1 of each period in a fixed sequence. Participants will also receive 500 mg of clarithromycin in period 4. Blood samples will be collected to evaluate the pharmacokinetic parameters. Participants' safety will be monitored throughout the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Study to Evaluate the Absolute Bioavailability of Intranasal and Oral Esketamine and the Effects of Clarithromycin on the Pharmacokinetics of Intranasal Esketamine in Healthy Subjects
Study Start Date : January 2015
Actual Primary Completion Date : April 2015
Actual Study Completion Date : April 2015

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Esketamine Regimen
All participants will first receive 28 milligram (mg) of esketamine as a single, 40-minute, intravenous infusion on Day 1 of Period 1, followed by 84 mg of esketamine solution as a single, oral dose on Day 1 of Period 2, followed by 84 mg of intranasal esketamine on Day 1 of Period 3 and then 500 mg of clarithromycin twice daily on Days -3, -2, -1, 1, and 2 of Period 4 and 84 mg of intranasal esketamine on Day 1 of Period 4. Each period will be separated by a washout period of up to 21 days in between.
Drug: Esketamine
28 mg of esketamine as a single, 40-minute, intravenous infusion on Day 1 of Period 1, 84 mg of esketamine solution as a single, oral dose on Day 1 of Period 2, 84 mg of intranasal esketamine on Day 1 of Period 3 and on Day 1 of Period 4.
Drug: Clarithromycin
500 mg of clarithromycin twice daily on Days -3, -2, -1, 1, and 2 of Period 4.



Primary Outcome Measures :
  1. Maximum Plasma Concentration (Cmax) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    The Cmax is the maximum plasma concentration.

  2. Time to Reach Maximum Plasma Concentration (Tmax) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    The Tmax is time to reach the maximum plasma concentration.

  3. Area Under the Plasma Concentration-time Curve From Time 0 to 12 Hours (AUC12h) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 hour (hr) post-dose on Day 1 in all periods ]
    The (AUC12h) is the area under the plasma concentration-time curve from time 0 to 12 hours Post-dose.

  4. Area Under the Plasma Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration AUC(0-last) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    The (AUC [0-last]) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration.

  5. Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC [0-infinity]) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    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(0-last) and C(0-last)/lambda(z), wherein AUC(0-last) is the area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentrations; C(0-last) is the last observed quantifiable concentration; and lambda(z) is elimination rate constant.

  6. Percentage of Area Under the Plasma Concentration-time Curve Obtained by Extrapolation (%AUC [infinity,ex]) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    Percentage of area under the plasma concentration-time curve obtained by extrapolation (%AUC[inf,ex]) is calculated by dividing the difference of AUC(0-infinity) and AUC(0-last) by AUC(0-infinity) and then multiplying by 100 (AUC[0-infinity] - AUC[0-last])*100/AUC[0-infinity].

  7. Elimination Half-life (t1/2) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    Elimination half-life (t [1/2]) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).

  8. Rate Constant (Lambda[z]) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    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.

  9. Absolute Bioavailability (Fabs) of Esketamine [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    The absolute bioavailability (Fabs) based on AUC(0-last) and AUC(0-inf) and estimated as 100*Test/Reference, where Test is defined as the pharmacokinetic parameters of oral esketamine and intranasal esketamine without clarithromycin and Reference is defined as intravenous esketamine.

  10. Relative Bioavailability of Esketamine (Frel) [ Time Frame: Pre-dose, 0.25, 0.33, 0.5, 0.66, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 18 hour (hr) post-dose on Day 1; 24, 36 hr post-dose on Day 2; 48 hr post-dose on Day 3 in all periods ]
    The relative bioavailability (Frel) based on Cmax, AUC(0-last), and AUC(0-inf) and estimated as 100*Test/Reference, where Test is defined as the pharmacokinetic parameters of intranasal esketamine and Reference is defined as intranasal esketamine + clarithromycin.

  11. Number of Participants With Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Throughout the duration of study (approximately up to 98 days) ]
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • For women of childbearing potential, must have a negative serum beta-human chorionic gonadotropin (hCG) pregnancy test at screening; and a negative urine pregnancy test on Day -1 of Period 1
  • If a man, must agree to use an adequate contraception method as deemed appropriate by the investigator (example, vasectomy, double-barrier, partner using effective contraception) and to not donate sperm during the study and for 3 months after receiving the last dose of study drug
  • 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
  • Participants with blood pressure (after the participant is supine for 5 minutes) between 90 and 140 millimeter of mercury (mmHg) systolic, inclusive, and no higher than 90 mmHg diastolic
  • Participants should be comfortable with self-administration of intranasal medication and able to follow instructions provided

Exclusion Criteria:

  • Participants diagnosed with a psychiatric disorder including but not limited to psychotic, bipolar, major depressive, or anxiety disorder
  • Participants with clinically significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, hematologic disease, coagulation disorders (including any abnormal bleeding or blood dyscrasias), lipid abnormalities, significant pulmonary disease, including bronchospastic respiratory disease, diabetes mellitus, renal or hepatic insufficiency, thyroid disease, neurologic disease, infection, hypertension or vascular disorders, 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
  • Participants with clinically significant abnormal values for hematology, clinical chemistry (particularly potassium or magnesium levels below the normal laboratory range), or urinalysis at screening or at admission to the study center (Day -1 of Period 1) as deemed appropriate by the investigator
  • Participants with clinically significant abnormal physical examination and vital signs at screening or at admission to the study center (Day -1 of Period 1) as deemed appropriate by the investigator
  • Participants with history of drug or alcohol abuse disorder within the past 1 year, or a reason to believe a participant has such a history

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): NCT02343289


Locations
Belgium
Merksem, Belgium
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: NCT02343289     History of Changes
Other Study ID Numbers: CR106240
ESKETINTRD1009 ( Other Identifier: Janssen Research & Development, LLC )
2014-004055-31 ( EudraCT Number )
First Posted: January 21, 2015    Key Record Dates
Last Update Posted: September 28, 2015
Last Verified: September 2015

Keywords provided by Janssen Research & Development, LLC:
Healthy
Pharmacokinetics
Esketamine
JNJ-54135419

Additional relevant MeSH terms:
Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors