Proof of Concept Study Evaluating the Efficacy and Safety of MIJ821 in Patients With Treatment-resistant Depression

Study Overview
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Brief Summary
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This study evaluated the efficacy and safety of the compound MIJ821 compared to placebo in patients aged from 18 to 65 years diagnosed with treatment-resistant depression. The study was conducted in the US and in Europe (Spain). The MIJ821 was administered via infusion on a weekly or bi-weekly basis. The efficacy was measured after 24 hours using a specific golden standard scale, the Montgomery-Asberg Depression Rating Scale. The study duration was 6 weeks of treatment plus 1 month of follow up period.

Detailed Description
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This was a non-confirmatory, multi-center, 6-treatment arm in European (Spain) and 5-treatment arm in the US (no ketamine arm), randomized, subject and investigator blinded, parallel-group, placebo-controlled study in patients with treatment-resistant depression. The total duration for each subject in the study was maximum 14 weeks: a screening period of maximum 4 weeks, a 36-day treatment period and a 5-week follow-up period.

Official Title
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A Multi-center, Randomized, subject-and Investigator Blinded, Placebo-controlled, Active Comparator, Parallel-group Proof of Concept Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of MIJ821 in Patients With Treatment-resistant Depression

Conditions
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Depressive Disorder, Treatment-Resistant

Intervention / Treatment
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* Drug: MIJ821
* Drug: Placebo
* Drug: Ketamine


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Signed informed consent. Male and female subjects, 18 to 65 years of age (inclusive) at screening. SCID-based DSM-5 defined major depressive episode at the time of screening Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 24 at screening and baseline Failure to respond to two or more antidepressant treatments, where two failed treatments are of two different antidepressants and at least one of which is in the current depressive episode, with adequate dose and duration (≥ 8 weeks duration, doses defined per agent), as identified by the Maudsley Treatment Inventory, and prior psychiatric history, assessed by the investigator, and further documented by medical records and/or third party report (family, friends, clinician-treaters) where available If patients are taking any type of psychotropic drugs, a stable dose of psychotropic drugs at screening is defined as no changes in dose or type of antidepressants, antipsychotics, or mood stabilizers for at least 2 weeks prior to screening, if applicable. No new antidepressant initiated 4 weeks or less before baseline, and 6 weeks or less before baseline if subject is initiated on fluoxetine At least one prior clinical depressive episode (recurrent major depressive disorder), as identified by prior psychiatric history assessed by the investigator, and further documented by medical records and third party report (family, friends, clinician-treaters) where available. Able to communicate well, and to understand and comply with study requirements Key Exclusion Criteria: Any current diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder at screening. Current alcohol or substance use disorder (including marijuana and prescribed amphetamine)) meeting DSM-5 criteria, within the past month at baseline. Nicotine and caffeine use disorders will not be considered as exclusionary. Prior suicidality caused by or associated with ketamine, as identified by prior psychiatric history assessed by the investigator, and augmented by medical records and third party report (family, friends, clinician-treaters) where available. Acute serious and/or imminent suicidal ideation and/or intent within the prior 2 weeks, or any suicide attempt within the prior 4 weeks at screening. Mild to moderate suicidal ideation, using the Sheehan Suicidal Ideation Scale and not meeting the above definition, is not an exclusion criterion. Use of other investigational drugs within 30 days or 5 half-lives of randomization, whichever was longer; or longer if required by local regulations at baseline Current pregnancy or lactation. Positive HIV, Hepatitis B or C test. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment baseline History of multiple and recurring allergies or allergy to the investigational compound/compound class being used in this study. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 3 years, regardless of whether there is evidence of local recurrence or metastases. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 1 week after stopping of investigational drug. History of hypersensitivity to any of the study treatments or excipients or to drugs similar to chemical classes that affect NMDA receptor. Current diagnosis of borderline personality disorder or antisocial personality disorder, based on DSM-5 criteria. Current acute depressive episode lasting longer than two years continuously, defined as no two week or longer period where depressive symptoms are subsyndromal in severity for a full DSM-5 acute major depressive episode. Considered by the investigator, for any other reason, to be an unsuitable candidate for the study.

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: This is a non-confirmatory, multi-center, 6-treatment arm in the EU countries and 5-treatment arm in the USA (no ketamine arm), randomized, subject and investigator blinded, parallel group, placebo controlled study in treatment-resistant depression patients. The study allows for the inclusion of subjects seeking treatment for their disease from both an 'inpatient' or 'outpatient' clinic setting.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MIJ821 low dose weekly<br>Infusion. MIJ821 low dose weekly - 0.16 mg/kg | Drug: MIJ821<br>* Different dosages and different regimen for MIJ821<br>|
| Experimental: MIJ821 low dose bi-weekly<br>Infusion. MIJ821 low dose bi-weekly - 0.16 mg/kg | Drug: MIJ821<br>* Different dosages and different regimen for MIJ821<br>|
| Experimental: MIJ821 high dose weekly<br>Infusion. MIJ821 high dose weekly - 0.32 mg/kg | Drug: MIJ821<br>* Different dosages and different regimen for MIJ821<br>|
| Experimental: MIJ821 high dose bi-weekly<br>Infusion. MIJ821 high dose bi-weekly - 0.32 mg/kg | Drug: MIJ821<br>* Different dosages and different regimen for MIJ821<br>|
| Placebo Comparator: Placebo weekly<br>Infusion. Placebo weekly | Drug: Placebo<br>* Infusion<br>|
| Active Comparator: Ketamine 0.5 mg/kg weekly<br>Infusion. Ketamine 0.5 mg/kg weekly | Drug: Ketamine<br>* Infusion<br>* Other names: Ketamine dose to be capped at 40 mg/day for patients over 80 kg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 24 Hrs | Efficacy. To assess change from baseline in the total MADRS score. The efficacy of MIJ821 in treatment-resistant depression will be compared to the placebo after single dose administration. MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment: 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. | Baseline, and at 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 48 Hrs | Efficacy. To assess change from baseline in the total MADRS score. The efficacy of MIJ821 in treatment-resistant depression will be compared to the placebo after single dose administration. MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment: 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. | Baseline, and at 48 hours | 
| Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at Week 6 | Efficacy. To assess change from baseline in the total MADRS score. The efficacy of MIJ821 in treatment-resistant depression will be compared to the placebo after single dose administration. MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment: 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. | Baseline, and at Week 6 | 
| Change From Baseline in the Young Mania Rating Scale | To assess risk of mania induction. The Young Mania Rating Scale has 11 items and is based on the patient's subjective report of his/her clinical condition over the previous 48 hours. There are 4 items that are scored from 0 to 8 (irritability, speech, thought content, and disruptive/aggressive behavior) and the remaining items are scored from 0 to 4. Higher scores indicate more severe mania. The total clinical score was calculated as the summation of the individual subscale scores. The maximum for the total YMRS score is 60. The range is 0 to 60 with the higher score indicating more severe symptoms. | Baseline, 24 hours, and 6 weeks (day 43) | 
| Bech-Rafaelsen Melancholia Scale | To assess efficacy in the melancholic subtype of depression. Depression scales are used primarily to measure changes, for example, to evaluate the efficacy of treatment with antidepressants. The Bech-Rafaelsen Melancholia Scale (BRMS) is a frequently used clinician rating scale to assess the severity of depression over the past 3 days. Each of the 11 BRMS items is operationally defined on a five-point scale (0-4); hence, the total score ranges from 0 to 44, higher scores indicating greater severity of depression. | Baseline, 24 hours, 48 hours and 6 weeks (Day 43) | 
| PK Properties of MIJ821 in Plasma - Cmax (ng/mL) | To assess MIJ821 pharmacokinetics in plasma described by Cmax. A single, sparse PK measurement was taken on Day 1. | Day 1 | 
| PK Properties of MIJ821 in Plasma - Tmax (ng/mL) | To assess MIJ821 pharmacokinetics in plasma described by Tmax. A single, sparse PK measurement was taken on Day 1. | Day 1 | 
| PK Properties of MIJ821 in Plasma - AUClast (h*ng/mL) | To assess MIJ821 pharmacokinetics in plasma described by AUClast (h*ng/mL). A single, sparse PK measurement was taken on Day 1. | Day 1 | 
| PK Properties of MIJ821 in Plasma - AUC0-24h (h*ng/mL) | To assess MIJ821 pharmacokinetics in plasma described by AUC0-24h (h*ng/mL). A single, sparse PK measurement was taken on Day 1. | Day 1 | 
| Change From Baseline in the CORE Melancholia Total Scale | To assess efficacy in melancholic subtype of depression. This scale is an 18 item scale, with a 6 item component capturing cognitive impairment and two motoric scales capturing psychomotor retardation (7 items) and psychomotor agitation (5 items). A cut-off score of 8 or more has been shown to ifferentiate melancholic from non-melancholic depression, with higher scores representing a greater probability of melancholic depression. (Parker and McCraw 2017). The total clinical score was calculated as the summation of the individual subscale scores. The maximum for the total CORE Melancholia score is 54. The range is 0 to 54 with the higher score indicating more severe symptoms. | Baseline, 24 hours, 48 hrs, and 6 weeks (day 43) | 
| Summary of Adverse Events | Summary of Adverse Events | Adverse events were reported from first dose of study treatment until end of study treatment plus 30 post treatment, up to a maximum duration of 66 days. | 
| Clinician-Administered Dissociative States Scale | To assess safety and tolerability, especially dissociative side effects. The Clinical-Administered Dissociative States Scale (CADSS) is a questionnaire that assesses dissociative effects. Each item is scored from 0 to 4 and individual scores are to be summed to obtain a total score ranging from a minimum of 0 to a maximum of 80. Higher scores represent a more severe condition. | Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43) | 
| Change From Baseline in the Dissociative Experiences Total Score | The Dissociative Experiences Scale (DES) consists of twenty-eight questions about experiences the subject has experienced in his/her daily life. The subject determines to what degree he/she has been facing the situation by selecting a percentage from 0% (never) to 100% (always), with 10% increments in between. Higher scores mean higher severity. | Baseline, 24 hours, 48 hrs, and 6 weeks (day 43) | 
| Sheehan Suicidality Tracking Scale - (SSTS) | Sheehan suicidality tracking scale(S-STS) is a fourteen-item (up to 22) scale. Each item in the S-STS is scored on a 5-point Likert scale (0=not at all, 1= a little, 2=moderately, 3=very, and 4=extremely). Data from the S-STS will be analyzed as individual item scores, suicidal ideation subscale score (sum of scores from items 2, 3 and 4, plus score from item 5 if ≤1), suicidal behavior subscale score (sum of scores from items 6, 7a and 8, plus score from item 5 if >1). Higher scores represent a more severe condition. | Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43) | 
| Percentage of Participants With Treatment Remissions (MADRS<7) | Percentage of Participants with treatment remissions as assessed via (MADRS<7) | 24 hours, 48 hours, and 6 weeks (Day 43) | 
| Change From Baseline in the Total Hamilton Anxiety Scale | The Hamilton Anxiety Rating Scale (HAM-A) measures psychic anxiety and somatic anxiety symptoms based on a clinical assessment and patient interview. The scale has 14 items, with each item rated from 0-4, ranging from not present to very severe. A maximum score of 56 indicates the most severe case. (Hamilton 1959). | Baseline, and at 6 weeks (day 43) | 
| Summary Statistics of Total Hamilton Anxiety Scale - Change From Baseline | The Hamilton Anxiety Rating Scale (HAM-A) measures psychic anxiety and somatic anxiety symptoms based on a clinical assessment and patient interview. The scale has 14 items, with each item rated from 0-4, ranging from not present to very severe. A maximum score of 56 indicates the most severe case. (Hamilton 1959). | Change from baseline at week 6 (Day 43) | 
| Change From Baseline in the Total Koukopoulos Mixed Depression Rating Scale | The Koukopoulos Mixed Depression Rating Scale (KMDRS) assesses the excitatory or mixed nature in patients suffering from a Major Depressive Episode (MDE) as defined by DSM-5 criteria. This scale is meant to be used in conjunction with another scale that assess typical depression and anxiety symptoms. The scale contains 14 items to be evaluated by clinical assessment and patient interview on symptoms potentially experienced over the past week. Overall score increases with severity of symptoms and has a maximum score of 51. (Sani et al 2018). | Baseline, 24 hours, 48 hrs, and 6 weeks (day 43) | 
| Responders (>50% Improvement in Bech-Rafaelsen Melancholia Scale) and Melancholia and Mixed Depression Checklist Factor. | Percentage of Participants who responded. The first mixed depression checklist, created by Koukopoulos, has 8 criteria, which are marked as present or absent. If 3 or more criteria are marked present, then mixed depression would be diagnosed. The second mixed depression checklist, created by Angst, lists the 7 criteria for mania from DSM-5, which are marked as present or absent. If 3 or more criteria are marked present, excluding any duration criterion, then mixed depression would be diagnosed. The melancholia checklist, created by Ghaemi for this study, has 4 criteria, which are marked as present or absent. If 3 or more criteria are marked present, then melancholia would be diagnosed. | 24 hours, 48 hours, and 6 weeks (Day 43) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory Depression, Therapy-Resistant Depression, Treatment Resistant Depression, MDE, MDD, Major depressive disorder (MDD), clinical depression, major depression, unipolar depression, unipolar mood disorder, depression, the blues, mood disorder