A Study of CLE-100 (Oral Esketamine) in Addition to Standard Antidepressant Drug for Major Depressive Disorder - CLEO Study

Study Overview
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Brief Summary
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The clinical trial is a Phase 2, double-blind, randomized, placebo controlled study in Major Depressive Disorder (MDD) participants currently treated with antidepressant therapy. The objective of the study is to assess CLE-100 for the treatment of MDD in participants currently treated with standard antidepressant therapy.

Detailed Description
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CLEO study is performed in two parts (part A and Part B). The sponsor is currently recruiting only for the Part B of the study. Part A will be an inpatient study to assess the safety, tolerability, and pharmacokinetics of CLE-100 (oral esketamine) in MDD participants currently treated with an antidepressant drug. It will include a screening phase (up to 35 days), a 1 week inpatient double-blind treatment phase and an outpatient post treatment safety follow-up phase of 1 week after last study drug administration. Part B will be a study to assess the safety and efficacy of CLE-100 (oral esketamine) in MDD participants currently treated with an antidepressant drug with inadequate response to standard antidepressant therapy. The participants will remain on their current antidepressant therapy with no dose change during the study.

Official Title
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A Two-Part Study of CLE-100 as an Adjunct Therapy in Subjects With Major Depressive Disorder

Conditions
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Adjunctive Treatment of Major Depressive Disorder

Intervention / Treatment
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* Drug: CLE-100
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Part A - Inclusion Criteria: Male or female between 18 to 60 years of age Primary diagnosis of MDD, without psychotic features according to DSM-5 and supported by the Mini International Neuropsychiatric Interview (MINI) MADRS score of at least 18 at Screening Treatment with stable dose of the current antidepressant therapy for at least 4 weeks for the current major depressive episode (MDE) Body mass index (BMI) between 18 and 40 kg/m2, inclusive Is able and competent to read and sign the informed consent form (ICF). Part A - Exclusion Criteria: History of substance use disorder per DSM-5 criteria, except for tobacco use disorder History or current diagnosis of bipolar disorder, schizophrenia, schizoaffective disorders, binge eating disorder dementia, delirium, amnesia, or any other significant cognitive disorder Posttraumatic stress disorder, obsessive compulsive disorder, or any other mental disorder (including personality disorders) Has any medical condition for which an increase in blood pressure or intracranial pressure poses a serious risk Female of childbearing potential without appropriate contraceptive means, pregnant or breastfeeding Part B - Inclusion Criteria: Male or female between 18 to 65 years of age Primary diagnosis of MDD without psychotic features according to DSM-5 and supported by the Mini International Neuropsychiatric Interview (MINI) MADRS score of at least 24 at Screening. At least 2 inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE) Current MDE for at least 12 weeks BMI between 18 and 40 kg/m2, inclusive. Is able and competent to read and sign the ICF. Part B - Exclusion Criteria: Inadequate response to more than 5 treatment courses of antidepressant medication therapy during the current MDE Current MDE for longer than 5 years. 3. Has a current substance use disorder or history of any substance use disorder per DSM-5 criteria within 12 months prior to Screening, except for tobacco use disorder. Has a history or current diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorders. Has dementia, delirium, amnesia, or any other significant cognitive disorder. Has posttraumatic stress disorder, obsessive compulsive disorder, or any other mental disorder (including personality disorders, eating disorders, etc.). Has any medical condition for which an increase in blood pressure or intracranial pressure poses a serious risk. Has been randomized in Part A of this study. Is a female of childbearing potential pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Part A - 15 patients, 2 arms, parallel; Part B - 122 patients, 2 arms, parallel
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - CLE-100 (oral esketamine)<br>Part A: 1 oral tablet of CLE-100 once daily for 1 week. | Drug: CLE-100<br>* 1 tablet of CLE-100 administered once daily<br>|
| Placebo Comparator: Part A - Placebo<br>Part A: 1 oral tablet of Placebo once daily for 1 week. | Drug: placebo<br>* 1 tablet of placebo administered once daily<br>|
| Experimental: Part B - CLE-100 (oral esketamine)<br>Part B: 1 oral tablet of CLE-100 once daily for 4 weeks. | Drug: CLE-100<br>* 1 tablet of CLE-100 administered once daily<br>|
| Placebo Comparator: Part B - Placebo<br>Part B: 1 oral tablet of Placebo once daily for 4 weeks. | Drug: placebo<br>* 1 tablet of placebo administered once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A - Frequency of adverse events |  | 14 days | 
| Part A - Self-Administered Karolinska Sleepiness Scale | The Karolinska Sleepiness Scale is a single-item, subjective, self-reported instrument measuring sleepiness on a 9-point Likert scale (1 to 9), where a higher value represents a worse outcome. | 7 days | 
| Part A - Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) | The MOAA/S will be used to measure treatment-emergent sedation. The MOAA/S is a widely used clinician-administered measure of alertness/sedation for clinical trials. The MOAA/S measures the alertness/sedation spectrum on a 6-point scale (0 to 5) based on verbal cues, where a higher value represents a better outcome. | 7 days | 
| Part A - Clinician-Administered Dissociative Symptoms Scale (CADSS) | The CADSS will be administered to assess treatment-emergent dissociative symptoms. The CADSS is a 23-item instrument that is clinician-administered. Each item is scored on a 5-point scale (0 to 4. A higher value represents a worse outcome. The CADSS total score ranges between 0 and 92. | 7 days | 
| Part A - Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS will be performed to assess suicidal ideation and behavior. The C-SSRS is an instrument used to assess suicide risk by measuring symptoms of suicidal ideation, self-harm, and suicidal behavior that is administered by trained personnel. The suicidal ideation is evaluated with a yes/no questionnaire and the suicidal behavior severity is scored on a 6-point scale (0 to 5) where a higher value represents a more severe behavior. | 7 days | 
| Part A - Four-items positive subscale from the Brief Psychiatric Rating Scale (BPRS) | Four items of the BPRS will be administered to assess treatment-emergent psychotic symptoms. The BPRS is a widely used, clinician-administered instrument that involves 4 subscales: Negative Symptoms, Positive Symptoms, Manic-Hostility, and Anxiety/Depression. The 4-item Positive Symptoms subscale of the BPRS will be used to screen for potential psychiatric symptoms (suspiciousness, hallucinations, unusual thought content, and conceptual disorganization). Each item is scored on a 7-point scale (1 to 7). where a higher value represents a worse outcome. The 4 items BPRS total score ranges between 4 and 28. | 7 days | 
| Part A - 20-item Physician Withdrawal Checklist (PWC-20) | The PWC-20 is a clinician-administered assessment to evaluate potential withdrawal symptoms following cessation of the double-blind treatment. The PWC-20 is a shortened version of the original 35-item instrument used to determine withdraw symptoms in subjects following discontinuation of anxiolytics. The items are evaluated on a 4-point scale (0 to 3) where a higher value represents a worse outcome. The total score ranges between 0 to 60. | 14 days | 
| Part A - Cognitive function evaluated by Cogstate battery | The Cogstate battery of cognitive tests will be used to measure psychomotor function, attention, visual learning, and working memory. The Cogstate battery will include the following tests: Detection Test, Identification Test, One Back Test, Groton Maze Test. | 7 days | 
| Part A - Digit Symbol Substitution Test (DSST) | The DSST is a psychometric test assessing the integrity of executive function, processing speed, attention, spatial perception, and visual scanning, which are functions required for driving, and will be performed repeatedly. The DSST is a valid and sensitive instrument to evaluate cognitive dysfunction and changes in cognitive function. The DSST is a timed test taken by the subject and scored based on both the number of correct answers and the speed at which they were determined. The score ranges between 0 to 135. | 7 days | 
| Part A - Pharmacokinetics of CLE-100 (Cmax) | Maximum observed plasma concentration (Cmax) | 7 days | 
| Part A - Pharmacokinetics of CLE-100 (Tmax) | Time of maximum observed plasma concentration (Tmax) | 7 days | 
| Part A - Pharmacokinetics of CLE-100 (AUC) | Area under the concentration curve | 8 days | 
| Part B - Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score | The MADRS is a validated clinician-administered measurement of depression severity commonly used in clinical trials of depression treatments to select subjects and assess efficacy. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B - Change from baseline in Symptoms of Depression Questionnaire (SDQ) score | The SDQ is a 44-item self-report scale for the assessment of MDD that includes assessments for irritability, anger attacks, and anxiety symptoms. Higher scores represent a more severe condition. | 29 days | 
| Part B - Change from baseline in Sheehan Disability Scale (SDS) | The SDS is a 3-item, self-completion instrument to assess functional impairments associated with work/school, social life and leisure activities, and family life and home responsibilities utilizing a 10-point scale. | 29 days | 
| Part B - Change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) score | The MADRS is a validated clinician-administered measurement of depression severity commonly used in clinical trials of depression treatments to select subjects and assess efficacy. The test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | 15 days | 
| Part B - Change from baseline in Clinical Global Impression - Severity (CGI-S) score | The CGI-S is a well-known and frequently used clinician-administered instrument for the assessment of MDD that weighs the clinical impact of the identified symptom(s) on behavior and function. The CGI-S grades measures of psychopathology on a scale from 1 to 7. | 29 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDD, depression, depressive disorder, major depression, adjunct therapy, oral, esketamine