An Open-label, Adaptive Design, Positron Emission Tomography Study in Healthy Male Participants to Characterize Receptor Occupancy by MIJ821 in the Brain

Study Overview
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Brief Summary
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The purpose of this study is to confirm binding of MIJ821 to the NR2B-containing NMDA receptors in the human brain and assess the PC-RO relationship over time using positron emission tomography (PET).

Detailed Description
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This is a Phase I, open-label, adaptive design study in healthy male participants using PET imaging with the radioligand [11C]Me-NB1 to measure occupancy of the NR2B-containing NMDA receptors by MIJ821. This exploratory study will be performed at a single clinical site and a separate PET imaging site. Up to 10 participants will be enrolled into 5 sequential cohorts. Each participant will receive a single dose of MIJ821 as an i.v. infusion. As part of the adaptive design, the dose of MIJ821 will be changed across cohorts to achieve the primary study objective in the smallest possible number of participants. After confirming eligibility during screening, each participant will undergo a baseline PET scan. Each participant will receive a single dose of i.v. MIJ821 during the treatment period, followed by up to two post dose PET scans. Post dose safety assessments will be performed up to End of Study visit which will happen once between Day 9 and Day 15.

Official Title
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An Open-label, Adaptive Design Study in Healthy Male Participants to Characterize the Occupancy of NR2B Subunit Containing NMDA Receptors in the Brain Following a Single Intravenous Dose of MIJ821 Using Positron Emission Tomography (PET) With the Radioligand [11C]Me-NB1

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: MIJ821


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent must be obtained prior to participation in the study Healthy males, aged 23 to 55 years (inclusive), and in good health as determined by past medical history, physical and neurological examination, vital signs, electrocardiogram, and laboratory tests at Screening and Baseline (whenever applicable) At screening and at baseline (Day -1), vital signs after 3 minutes resting (in sitting position during screening and supine position during baseline) must be within the following ranges: Body temperature (otic) from 35.0 °C to 37.5 °C, inclusive Systolic blood pressure (BP) from 90 to 139 mmHg, inclusive Diastolic BP from 50 to 89 mmHg, inclusive. Pulse rate from 50 to 90 beats per minute, inclusive Participants must weigh at least 50 kg to participate in the study and must have a body mass index (BMI) within the range of 18.0 to 29.9 kg/m² at screening. BMI = body weight (kg) / height2 (m2) Participants must be able to communicate well with the Investigator and to comply with the requirements of the entire study, including adhering to study restrictions and visit schedule Key Exclusion criteria: Hypersensitivity to NMDA antagonists (MIJ821 or other compounds with similar mechanism of action, like ketamine or compounds with similar chemical structure to ketamine) or to any excipients, local anesthetics, or anticoagulants used in this study. Any significant illness, including infectious diseases, which has not resolved within 2 weeks prior to baseline. Any of the following ECG abnormalities at Screening or Baseline: PR interval outside 110-200 ms QRS duration outside 70-120 ms Resting heart rate in sinus rhythm outside 50-90 bpm QTcF > 450 ms Exposure to ionizing radiation as part of a research study, which, in addition to the exposure from this study, would lead to a total effective dose of more than 10 mSv in a period of one year. Any history of neurological disorders, including, but not limited to any of the followings: Any history of stroke or known cerebrovascular disorders (e.g. aneurysm or arteriovenous malformation) or known aneurysmal vascular disease in other location (e.g. aorta) Any history or presence of epilepsy or of seizures or convulsions of any kind. Any history of head trauma leading to permanent sequelae or history of head trauma leading to clinically significant but transient symptoms within 2 years of baseline. Score yes on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months from screening, or yes on any item of the Suicidal Behavior section, except for the Non-Suicidal Self-Injurious Behavior (item also included in the Suicidal Behavior section), if this behavior occurred in the past 2 years. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 90 days following dosing. A condom is required for all sexually active male participants for 90 days following dosing (including vasectomized men) to prevent them from fathering a child AND to prevent delivery of the investigational drug via seminal fluid to their partner.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

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: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: There will be 5 Cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>MIJ821, starting dose | Drug: MIJ821<br>* MIJ821 will be administered as an i.v. infusion<br>|
| Experimental: Cohort 2<br>MIJ821, dose will be defined based on the results of the previous cohort(s). | Drug: MIJ821<br>* MIJ821 will be administered as an i.v. infusion<br>|
| Experimental: Cohort 3<br>MIJ821, dose will be defined based on the results of the previous cohort(s). | Drug: MIJ821<br>* MIJ821 will be administered as an i.v. infusion<br>|
| Experimental: Cohort 4<br>MIJ821, dose will be defined based on the results of the previous cohort(s). | Drug: MIJ821<br>* MIJ821 will be administered as an i.v. infusion<br>|
| Experimental: Cohort 5<br>MIJ821, dose will be defined based on the results of the previous cohort(s). | Drug: MIJ821<br>* MIJ821 will be administered as an i.v. infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Human Brain Receptor Occupancy and Plasma Concentration of MIJ821 | To evaluate the relationship between plasma concentration of MIJ821 and brain receptor occupancy by MIJ821 in healthy participants, by using positron emission tomography (PET) with [11C]Me-NB1 | Baseline PET Scan up to 15 days post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Binding parameters of [11C]-MeNB1 | To characterize the binding properties of [11C]-Me-NB1 in the human brain | Baseline PET scan up to 15 days post dose | 
| Percentage change in PET imaging outcome measures after treatment with MIJ821 compared to baseline and plasma concentration of MIJ821 | To evaluate the relationship between displacement of central (brain) radioligand binding and systemic (plasma) concentration of MIJ821 | Baseline PET scan up to 36 hours post dose | 
| Tmax will be calculated as a PK parameter of MIJ821 in plasma. | To assess the systemic pharmacokinetics (PK) of MIJ821 after a single intravenous (i.v.) dose in healthy participants | PK samples are collected at the end of i.v. infusion (Day 1) and at the beginning and end of each PET scan. Each cohort has 5 samples collected at various timepoints (dependent on time of PET scans) from i.v. infusion up to 5 days. | 
| AUC will be calculated as a PK parameter of MIJ821 in plasma | To assess the systemic pharmacokinetics (PK) of MIJ821 after a single intravenous (i.v.) dose in healthy participants | PK samples are collected at the end of i.v. infusion (Day 1) and at the beginning and end of each PET scan. Each cohort has 5 samples collected at various timepoints (dependent on time of PET scans) from i.v. infusion up to 5 days. | 
| Cmax will be calculated as a PK parameter of MIJ821 in plasma | To assess the systemic pharmacokinetics (PK) of MIJ821 after a single intravenous (i.v.) dose in healthy participants | PK samples are collected at the end of i.v. infusion (Day 1) and at the beginning and end of each PET scan. Each cohort has 5 samples collected at various timepoints (dependent on time of PET scans) from i.v. infusion up to 5 days. | 
| Number of adverse events and serious adverse events. | The occurrence of adverse events must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments (e.g., CADSS and C-SSRS). | Baseline up to Day 15, plus 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NR2B receptor modulator, Healthy subject, safety, pharmacokinetics receptor occupancy, PET scan, Major Depressive Disorder, adult