Safety and Pharmacokinetic Study of Inhaled Esketamine in Healthy Volunteers

Study Overview
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Brief Summary
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The planned study is to determine the pharmacokinetic properties of Esketamine and safety assessment with inhaled Esketamine after different number of inhalations and different dosing sequences within three parts of the study.

Detailed Description
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This is to be one-centre, single ascending dose and double-blind placebo controlled multiple dose three part study of Esketamine DPI (dry powder inhaler) in healthy volunteers. PART A is a single dose, open-label part with Esketamine DPI inhalations administered with dose escalation between cohorts. PART B is a single dose, open-label part with Esketamine DPI inhalations administered in different dosing sequences with dose escalation between cohorts. PART C is a multiple dose, double-blind, placebo-controlled part with Esketamine DPI inhalations administered in different cycles of treatment (with four dosing sequences within two weeks) with dose escalation between cohorts. Participants in this part will be randomized to receive Esketamine DPI or placebo in 3:1 ratio. Pharmacokinetic properties and safety of Esketamine DPI will be determined following different number of inhalations in PART A, different dosing sequences in PART B and different cycles of treatment in PART C.

Official Title
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One-centre Safety and Pharmacokinetics Phase I Study of Inhaled Esketamine in Healthy Volunteers With Two Single Ascending Dose and One Double-blind Multiple Ascending Dose Parts

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Esketamine DPI
* Drug: Esketamine DPI
* Drug: Esketamine DPI
* Drug: Placebo DPI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian female or male, Age: 18-55 years old, inclusive, Body-mass index (BMI): ≥18.5 kg/m^2 and <29.9 kg/m^2 Non-smoker and nonuser of tobacco products for at least 1 year before screening, Physical examination without any clinically relevant abnormality, Laboratory values not clinically significant, Volunteer (or his/her partner) of childbearing potential willingness to use acceptable forms of contraception. Exclusion Criteria: Known allergy or hypersensitivity to ketamine or its derivates and/or to any study product excipients, Any known significant current or past acute or chronic disease or condition, Participation in other clinical trial within 90 days preceding the screening, Blood drawn within 30 days prior to inclusion to the study (more or equal to 300mL), Positive results from pregnancy test for female participants, Lactation in women participants, Hypotension or hypertension in medical history, Narcotic, alcohol addiction or abuse, Participant who adhere to a special diet (e.g. low calories, vegetarian).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PART A<br>6 cohorts will receive single dose of Esketamine DPI administered with dose escalation between cohorts. | Drug: Esketamine DPI<br>* Participants will receive different number of consecutive Esketamine DPI inhalations, consider as a single dose. There will be dose escalation between cohorts.<br>|
| Experimental: PART B<br>4 cohorts will receive single dose of Esketamine DPI administered with dose escalation between cohorts. | Drug: Esketamine DPI<br>* Participants will receive different dosing sequences of Esketamine DPI inhalations, consider as a single dose. There will be dose escalation between cohorts. Number of Esketamine DPI inhalations within a dosing sequence will be defined based on results from PART A of the study. Dose: very low, low, medium, high.<br>|
| Experimental: PART C<br>4 cohorts will receive multiple dose of Esketamine DPI in two weeks' time administered with dose escalation between cohorts. | Drug: Esketamine DPI<br>* Participants will receive different cycle of treatment consisting of 4 dosing sequences administered within 2 weeks. There will be dose escalation between cohorts. Participants in this part will be randomized to receive Esketamine DPI or placebo in 3:1 ratio. Number of Esketamine DPI inhalations within a dosing sequence will be defined based on results from PART A and PART B of the study. Dose: very low, low, medium, high.<br>|
| Placebo Comparator: PART C placebo<br>4 cohorts will receive multiple dose of matching placebo in two weeks' time. | Drug: Placebo DPI<br>* Participants will receive different cycle of treatment consisting of 4 dosing sequences administered within 2 weeks. Participants in this part will be randomized to receive Esketamine DPI or placebo in 3:1 ratio. In each cohort, number of placebo inhalations within a dosing sequence will correspond to number of Esketamine DPI inhalations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax - maximum Esketamine plasma concentration | The maximum concentration of the Esketamine in plasma after drug administration, obtained directly from the measured concentrations. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| AUC (0-24) - area under the Esketamine plasma concentration-time curve from time 0 to 24 hours after study drug administration | The AUC(0-24) is a measure of total plasma exposure to the drug from time point zero to 24 hours after study drug administration. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Number of inhalations needed to achieve the assumed Esketamine antidepressive plasma concentration. |  | up to 24 hours after study drug administration in PART A | 
| Number of inhalations within dosing sequence needed to maintain the assumed Esketamine antidepressive plasma concentration. |  | up to 24 hours after study drug administration in PART B | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC (0-inf) - area under the Esketamine plasma concentration-time curve from time 0 to infinity time | The AUC(0-inf) is a measure of total plasma exposure to the drug from time point zero extrapolated to infinity. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Tmax - time to reach maximum Esketamine plasma concentration | The Tmax is time to reach the maximum plasma concentration (Cmax), obtained directly from the actual sampling times. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Kel -elimination rate constant | Kel will be estimated via linear regression of time versus log of concentration. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| T1/2 - plasma elimination half-life for Esketamine | T1/2 will be calculated as 0.693/Kel. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Cmax - maximum Esnorketamine plasma concentration | The maximum concentration of the Esnorketamine in plasma after drug administration, obtained directly from the measured concentrations. Esnorketamine is Esketamine's main metabolite. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| AUC (0-24) - area under the Esnorketamine plasma concentration-time curve from time 0 to 24 hours after study drug administration. | The AUC(0-24) is a measure of total Esnorketamine plasma exposure to the metabolite from time point zero to 24 hours after study drug administration. Esnorketamine is Esketamine's main metabolite. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Tmax - time to reach maximum Esnorketamine plasma concentration. | The Tmax is time to reach the maximum Esnorketamine plasma concentration (Cmax), obtained directly from the actual sampling times. Esnorketamine is Esketamine's main metabolite. | up to 24 hours after each study drug administration in PART A, B and C of the study. | 
| Number of participants with adverse events (AEs) and Serious Adverse Events (SAEs). | Participants during hospitalization will be closely observed to assure maximal safety and to collect occurrence of all adverse event. To follow-up on all study participants telephone calls with a request for information regarding their health condition will be made. All adverse events will be collected with special attention to occurrence of psychotomimetic and dissociative effects after study drug administration. | up to 7 days in PART A and PART B of the study and up to 25 days in PART C of the study. |