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

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03756129
• Collaborator: (none)
• Enrollment: 70
• Locations: 12
• Arms: 6
• Actual Duration (Months): 13.4
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder, Treatment-Resistant	Drug: MIJ821; Drug: Placebo; Drug: Ketamine	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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.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 (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Feb 8, 2019
• Actual Primary Completion Date: Mar 23, 2020
• Actual Study Completion Date: Mar 23, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 24 Hrs [Baseline, and at 24 hours]

   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.

Secondary Outcome Measures

1. Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 48 Hrs [Baseline, and at 48 hours]

   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.

2. Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at Week 6 [Baseline, and 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.

3. Change From Baseline in the Young Mania Rating Scale [Baseline, 24 hours, and 6 weeks (day 43)]

   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.

4. Bech-Rafaelsen Melancholia Scale [Baseline, 24 hours, 48 hours and 6 weeks (Day 43)]

   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.

5. PK Properties of MIJ821 in Plasma - Cmax (ng/mL) [Day 1]

   To assess MIJ821 pharmacokinetics in plasma described by Cmax. A single, sparse PK measurement was taken on Day 1.

6. PK Properties of MIJ821 in Plasma - Tmax (ng/mL) [Day 1]

   To assess MIJ821 pharmacokinetics in plasma described by Tmax. A single, sparse PK measurement was taken on Day 1.

7. PK Properties of MIJ821 in Plasma - AUClast (h*ng/mL) [Day 1]

   To assess MIJ821 pharmacokinetics in plasma described by AUClast (h*ng/mL). A single, sparse PK measurement was taken on Day 1.

8. PK Properties of MIJ821 in Plasma - AUC0-24h (h*ng/mL) [Day 1]

   To assess MIJ821 pharmacokinetics in plasma described by AUC0-24h (h*ng/mL). A single, sparse PK measurement was taken on Day 1.

9. Change From Baseline in the CORE Melancholia Total Scale [Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)]

   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.

10. 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.]

    Summary of Adverse Events

11. Clinician-Administered Dissociative States Scale [Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43)]

    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.

12. Change From Baseline in the Dissociative Experiences Total Score [Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)]

    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.

13. Sheehan Suicidality Tracking Scale - (SSTS) [Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43)]

    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.

14. Percentage of Participants With Treatment Remissions (MADRS<7) [24 hours, 48 hours, and 6 weeks (Day 43)]

    Percentage of Participants with treatment remissions as assessed via (MADRS<7)

15. Change From Baseline in the Total Hamilton Anxiety Scale [Baseline, and at 6 weeks (day 43)]

    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).

16. Summary Statistics of Total Hamilton Anxiety Scale - Change From Baseline [Change from baseline at week 6 (Day 43)]

    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).

17. Change From Baseline in the Total Koukopoulos Mixed Depression Rating Scale [Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)]

    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).

18. Responders (>50% Improvement in Bech-Rafaelsen Melancholia Scale) and Melancholia and Mixed Depression Checklist Factor. [24 hours, 48 hours, and 6 weeks (Day 43)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Birmingham	Alabama	United States	35294
2	Novartis Investigative Site	Garden Grove	California	United States	92845
3	Novartis Investigative Site	Oakland	California	United States	94607
4	Novartis Investigative Site	Bradenton	Florida	United States	34201
5	Novartis Investigative Site	Atlanta	Georgia	United States	30331
6	Novartis Investigative Site	Skokie	Illinois	United States	60076
7	Novartis Investigative Site	Rockville	Maryland	United States	20850
8	Novartis Investigative Site	Berlin	New Jersey	United States	08009
9	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
10	Novartis Investigative Site	Palma De Mallorca	Islas Baleares	Spain	07120
11	Novartis Investigative Site	Vitoria-Gasteiz	Pais Vasco	Spain	01004
12	Novartis Investigative Site	Barcelona		Spain	08006

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 10, 2019
• Statistical Analysis Plan - Jun 4, 2020

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03756129
• Other Study ID Numbers: CMIJ821X2201
• First Posted: Nov 28, 2018
• Last Update Posted: Oct 8, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: 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
• Additional relevant MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Treatment-Resistant; Ketamine

Study Results

Participant Flow

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Period Title: Overall Study
STARTED	11	10	10	9	10	20
COMPLETED	8	8	7	6	9	15
NOT COMPLETED	3	2	3	3	1	5

Baseline Characteristics

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly	Total
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly	Total of all reporting groups
Overall Participants	11	10	10	9	10	20	70
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 100%	9 90%	10 100%	9 100%	10 100%	20 100%	69 98.6%
>=65 years	0 0%	1 10%	0 0%	0 0%	0 0%	0 0%	1 1.4%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	48.6 (11.70)	53.7 (9.33)	42.9 (14.47)	46.6 (11.83)	52.3 (6.96)	44.8 (10.69)	47.7 (11.27)
Sex: Female, Male (Count of Participants)
Female	2 18.2%	5 50%	6 60%	6 66.7%	7 70%	9 45%	35 50%
Male	9 81.8%	5 50%	4 40%	3 33.3%	3 30%	11 55%	35 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%	1 1.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	3 27.3%	4 40%	4 40%	8 88.9%	0 0%	10 50%	29 41.4%
White	8 72.7%	6 60%	6 60%	1 11.1%	9 90%	9 45%	39 55.7%
More than one race	0 0%	0 0%	0 0%	0 0%	1 10%	0 0%	1 1.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 24 Hrs
Description	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.
Time Frame	Baseline, and at 24 hours

Outcome Measure Data

Analysis Population Description

Intent to Treat analysis set

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	21	19	10	20
Least Squares Mean (Standard Error) [Scores on a Scale]	-15.51 (1.9)	-12.98 (1.9)	-12.94 (2.7)	-7.27 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.16 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "Pooled MIJ821 0.16 mg/kg" minus "placebo". The MIJ821 treatment arms vs placebo are primary.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0013
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-8.25
	Confidence Interval	(2-Sided) 80%; -11.67 to -4.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.32 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "Pooled MIJ821 0.32 mg/kg" minus "placebo". The MIJ821 treatment arms vs placebo are primary.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0196
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.71
	Confidence Interval	(2-Sided) 80%; -9.22 to -2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at 48 Hrs
Description	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.
Time Frame	Baseline, and at 48 hours

Outcome Measure Data

Analysis Population Description

Intent to Treat analysis set. Please note that some participants missed some visits in the study, and thus data for this outcome measure were not collected for some participants.

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	19	16	4	19
Least Squares Mean (Standard Error) [Scores on a Scale]	-14.94 (2.2)	-15.25 (2.4)	-18.89 (4.8)	-7.88 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.16 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "Pooled MIJ821 0.16 mg/kg" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0130
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.06
	Confidence Interval	(2-Sided) 80%; -11.06 to -3.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.32 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "Pooled MIJ821 0.32 mg/kg" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0133
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-7.37
	Confidence Interval	(2-Sided) 80%; -11.57 to -3.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Total Score of the Montgomery Asberg Depression Rating Scale (MADRS) at Week 6
Description	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.
Time Frame	Baseline, and at Week 6

Outcome Measure Data

Analysis Population Description

Intent to Treat analysis set

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	8	8	8	6	9	17
Least Squares Mean (Standard Error) [Scores on a Scale]	-12.71 (3.4)	-14.08 (3.4)	-13.04 (3.5)	-10.68 (3.9)	-12.86 (3.3)	-7.62 (2.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.16 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "MIJ821 0.16 mg/kg weekly" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1082
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.09
	Confidence Interval	(2-Sided) 80%; -10.37 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ketamine 0.5 mg/kg Weekly, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "MIJ821 0.32 mg/kg weekly" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0993
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.42
	Confidence Interval	(2-Sided) 80%; -10.83 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Pooled MIJ821 0.32 mg/kg, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "MIJ821 0.16 mg/kg biweekly" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0598
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-6.46
	Confidence Interval	(2-Sided) 80%; -11.78 to -1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo Weekly, Placebo Weekly
	Comments	Comparison of adjusted arithmetic mean: Mean Difference: "MIJ821 0.32 mg/kg biweekly" minus "placebo".
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2491
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.06
	Confidence Interval	(2-Sided) 80%; -8.86 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in the Young Mania Rating Scale
Description	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.
Time Frame	Baseline, 24 hours, and 6 weeks (day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Adjusted arithmetic mean change from baseline at 24 hrs (n=11,10,10,9,10,20)	-1.41 (0.5)	-1.07 (0.5)	-1.66 (0.5)	-0.81 (0.5)	-1.56 (0.5)	-0.72 (0.3)
Adjusted arithmetic mean change from baseline at day 43 (n=8,8,8,6,9,17)	-1.28 (0.6)	-2.13 (0.7)	-0.65 (0.7)	-1.55 (0.7)	-1.80 (0.7)	-0.92 (0.4)

5. Secondary Outcome

Title	Bech-Rafaelsen Melancholia Scale
Description	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.
Time Frame	Baseline, 24 hours, 48 hours and 6 weeks (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Change at 24 hrs (n=11,10,10,8,9,20)	-11.9 (5.941)	-9.5 (4.625)	-7.9 (6.903)	-8.1 (4.612)	-7.7 (5.766)	-6.0 (5.262)
Change at 48 hrs (n=9,10,9,7,4,19)	-9.9 (5.326)	-8.0 (5.185)	-7.6 (8.383)	-8.0 (5.508)	-12.5 (7.853)	-6.7 (6.659)
Change at day 43 (n=8,8,8,6,9,17)	-8.6 (6.589)	-8.6 (5.423)	-7.6 (10.013)	-6.0 (9.338)	-8.9 (8.343)	-6.9 (5.988)

6. Secondary Outcome

Title	PK Properties of MIJ821 in Plasma - Cmax (ng/mL)
Description	To assess MIJ821 pharmacokinetics in plasma described by Cmax. A single, sparse PK measurement was taken on Day 1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Measure Participants	14	11
Mean (Standard Deviation) [ng/mL]	99.5 (47.8)	149 (63.4)

7. Secondary Outcome

Title	PK Properties of MIJ821 in Plasma - Tmax (ng/mL)
Description	To assess MIJ821 pharmacokinetics in plasma described by Tmax. A single, sparse PK measurement was taken on Day 1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Measure Participants	14	11
Median (Full Range) [hour]	0.683	0.667

8. Secondary Outcome

Title	PK Properties of MIJ821 in Plasma - AUClast (h*ng/mL)
Description	To assess MIJ821 pharmacokinetics in plasma described by AUClast (h*ng/mL). A single, sparse PK measurement was taken on Day 1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Measure Participants	14	11
Mean (Standard Deviation) [h*ng/mL]	496 (239)	738 (302)

9. Secondary Outcome

Title	PK Properties of MIJ821 in Plasma - AUC0-24h (h*ng/mL)
Description	To assess MIJ821 pharmacokinetics in plasma described by AUC0-24h (h*ng/mL). A single, sparse PK measurement was taken on Day 1.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Arm/Group Description	Pooled MIJ821 0.16 mg/kg	Pooled MIJ821 0.32 mg/kg
Measure Participants	13	11
Mean (Standard Deviation) [h*ng/mL]	462 (232)	713 (275)

10. Secondary Outcome

Title	Change From Baseline in the CORE Melancholia Total Scale
Description	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.
Time Frame	Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Adjusted arithmetic mean change from baseline at 24 hrs (n=4,3,4,3,9,8)	-4.76 (2.9)	-3.64 (3.6)	-3.93 (3.0)	1.38 (3.5)	-5.07 (2.0)	-3.61 (2.0)
Adjusted arithmetic mean change from baseline at 48 hrs (n=2,3,3,2,4,9)	-5.77 (3.9)	-2.82 (3.7)	-5.92 (3.2)	1.62 (4.0)	-6.68 (2.6)	-5.06 (1.9)
Adjusted arithmetic mean change from baseline at day 43 (n=3,2,3,2,8,8)	-5.79 (3.4)	-4.82 (4.4)	-7.24 (3.5)	-6.49 (4.3)	-9.01 (2.1)	-5.21 (2.1)

11. Secondary Outcome

Title	Summary of Adverse Events
Description	Summary of Adverse Events
Time Frame	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.

Outcome Measure Data

Analysis Population Description

safety analysis set

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
AEs, subjects with AEs	7 63.6%	6 60%	7 70%	6 66.7%	6 60%	7 35%
Study drug-related AEs	5 45.5%	5 50%	7 70%	5 55.6%	6 60%	5 25%
SAEs	0 0%	1 10%	0 0%	3 33.3%	0 0%	1 5%
AEs leading to discontinuation of study treatment	1 9.1%	0 0%	0 0%	2 22.2%	0 0%	1 5%
Study drug-related AEs leading to discontinuation of study treatment	0 0%	0 0%	0 0%	0 0%	0 0%	1 5%

12. Secondary Outcome

Title	Clinician-Administered Dissociative States Scale
Description	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.
Time Frame	Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Change at 24 hrs (n=11,10,10,8,10,20)	1.09 (5.262)	1.10 (2.726)	2.10 (3.414)	3.00 (3.703)	-0.50 (0.707)	-0.25 (0.716)
Change at 48 hrs (n=9,10,9,7,4,19)	-0.22 (0.667)	0.50 (2.369)	4.44 (10.394)	3.14 (3.976)	0.00 (0.00)	-0.16 (0.375)
Change at day 43 (n=8,8,8,6,9,17)	0.00 (1.927)	0.00 (0.00)	0.38 (1.061)	1.00 (2.449)	0.00 (1.118)	-0.18 (0.636)

13. Secondary Outcome

Title	Change From Baseline in the Dissociative Experiences Total Score
Description	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.
Time Frame	Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Adjusted arithmetic mean change from baseline at 24 hrs (n=11,10,10,9,10,20)	1.82 (1.0)	2.00 (1.1)	1.20 (1.1)	7.22 (1.1)	2.10 (1.1)	2.50 (0.8)
Adjusted arithmetic mean change from baseline at 48 hrs (n=9,10,9,7,4,19)	1.80 (1.1)	2.30 (1.1)	1.89 (1.1)	3.46 (1.2)	1.89 (1.4)	2.43 (0.8)
Adjusted arithmetic mean change from baseline at day 43 (n=8,8,8,6,9,17)	1.38 (1.1)	1.61 (1.1)	1.02 (1.1)	0.24 (1.3)	1.86 (1.1)	2.63 (0.8)

14. Secondary Outcome

Title	Sheehan Suicidality Tracking Scale - (SSTS)
Description	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.
Time Frame	Change from baseline at 24 hours, 48 hours, and 6 weeks (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Suicidal behavior subscale score - Change at 24 hrs (n=11,10,10,9,10,20)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.11 (0.333)	-0.10 (0.316)	0.00 (0.00)
Suicidal behavior subscale score - Change at 48 hrs (n=9,10,9,7,4,19)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)
Suicidal behavior subscale score - Change at day 43 (n=8,8,8,6,9,17)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	0.00 (0.00)	-0.11 (0.333)	0.12 (0.485)
Suicidal ideation subscale score - Change at 24 hrs (n=11,10,10,9,10,20)	-0.45 (0.820)	-0.50 (0.850)	-0.30 (0.675)	0.11 (1.269)	-0.40 (0.966)	-0.20 (0.523)
Suicidal ideation subscale score - Change at 48 hrs (n=9,10,9,7,4,19)	-0.22 (0.667)	-0.50 (0.850)	-0.33 (0.707)	-0.43 (0.787)	0.00 (0.00)	-0.16 (0.375)
Suicidal ideation subscale score - Change at day 43 (n=8,8,8,6,9,17)	-0.38 (0.744)	-0.13 (0.354)	-0.13 (1.126)	0.00 (1.265)	-0.11 (1.269)	0.12 (1.111)
SSTS total score - Change at 24 hrs (n=11,10,10,9,10,20)	-0.45 (0.820)	-0.50 (0.850)	-0.30 (0.675)	0.11 (1.764)	-0.50 (1.269)	-0.20 (0.523)
SSTS total score Change at 48 hrs (n=9,10,9,7,4,19)	-0.22 (0.667)	-0.50 (0.850)	-0.33 (0.707)	-0.57 (1.134)	0.00 (0.00)	-0.16 (0.375)
SSTS total score - Change at Day 43 (n=8,8,8,6,9,17)	-0.38 (0.744)	-0.13 (0.354)	-0.13 (1.126)	-0.17 (1.602)	-0.22 (1.563)	0.47 (2.503)

15. Secondary Outcome

Title	Percentage of Participants With Treatment Remissions (MADRS<7)
Description	Percentage of Participants with treatment remissions as assessed via (MADRS<7)
Time Frame	24 hours, 48 hours, and 6 weeks (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
% of participants with remission at 24 hrs (n=11,10,10,8,10,20)	9.1 82.7%	20.0 200%	0 0%	11.1 123.3%	20.0 200%	5.0 25%
% of participants with remission at 48 hrs (n=9,10,9,7,4,19)	22.2 201.8%	10.0 100%	11.1 111%	28.6 317.8%	25.0 250%	10.5 52.5%
% of participants with remission at Day 43 (n=8,8,8,6, 9,17)	25.0 227.3%	37.5 375%	0 0%	16.7 185.6%	22.2 222%	11.8 59%

16. Secondary Outcome

Title	Change From Baseline in the Total Hamilton Anxiety Scale
Description	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).
Time Frame	Baseline, and at 6 weeks (day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	8	8	8	6	8	17
Least Squares Mean (Standard Error) [Scores on a Scale]	-1.94 (2.0)	-5.69 (2.0)	-7.17 (2.0)	-3.83 (2.2)	-4.93 (2.0)	-4.80 (1.4)

17. Secondary Outcome

Title	Summary Statistics of Total Hamilton Anxiety Scale - Change From Baseline
Description	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).
Time Frame	Change from baseline at week 6 (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	8	8	8	6	8	17
Mean (Standard Deviation) [Scores on a Scale]	-2.6 (6.927)	-5.4 (4.565)	-6.8 (6.606)	-4.2 (9.432)	-5.4 (7.763)	-5.1 (5.651)

18. Secondary Outcome

Title	Change From Baseline in the Total Koukopoulos Mixed Depression Rating Scale
Description	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).
Time Frame	Baseline, 24 hours, 48 hrs, and 6 weeks (day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The number of participants analyzed varies from one visit to another because of missed visits and early terminations.

Arm/Group Title	MIJ821 0.16 mg/kg Weekly	MIJ821 0.16 mg/kg Biweekly	MIJ821 0.32 mg/kg Weekly	MIJ821 0.32 mg/kg Biweekly	Ketamine 0.5 mg/kg Weekly	Placebo Weekly
Arm/Group Description	MIJ821 0.16 mg/kg weekly	MIJ821 0.16 mg/kg biweekly	MIJ821 0.32 mg/kg weekly	MIJ821 0.32 mg/kg biweekly	Ketamine 0.5 mg/kg weekly	Placebo weekly
Measure Participants	11	10	10	9	10	20
Adjusted arithmetic mean change from baseline at 24 hrs (n=11,10,10,9,10,20)	-2.79 (0.9)	-2.38 (0.9)	-1.50 (1.0)	-2.46 (1.0)	-1.28 (1.0)	-2.33 (0.7)
Adjusted arithmetic mean change from baseline at 48 hrs (n=9,10,9,7,4,19)	-2.95 (1.0)	-1.03 (0.9)	-1.97 (1.0)	-3.43 (1.1)	0.01 (1.3)	-1.97 (0.7)
Adjusted arithmetic mean change from baseline at day 43 (n=8,8,8,6,9,17)	-1.18 (1.0)	-1.06 (1.0)	-1.55 (1.1)	-2.04 (1.2)	-1.68 (1.0)	-1.59 (0.7)

19. Secondary Outcome

Title	Responders (>50% Improvement in Bech-Rafaelsen Melancholia Scale) and Melancholia and Mixed Depression Checklist Factor.
Description	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.
Time Frame	24 hours, 48 hours, and 6 weeks (Day 43)

Outcome Measure Data

Analysis Population Description

Intent-to-treat analysis set. The sampling size for this outcome measure was too small to support inferential statistics; therefore, the results for this outcome measure were limited to this high-level summary table, where data for the 2 drugs were pooled (MIJ821, all doses and all dosage regimes) and Ketamine vs placebo.

Arm/Group Title	Koukopoulos	Angst	Ghaemi
Arm/Group Description	Koukopoulos Mixed Depression Rating Scale	Mixed depression checklist, created by Angst	Melancholia checklist, created by Ghaemi
Measure Participants	9	9	9
% of participants who responded at 24 hrs - drugs (n=5,5,5)	40.0 363.6%	0 0%	20.0 200%
% of participants who responded at 24 hrs - placebo (n=1,1,1)	0 0%	0 0%	100 1000%
% of participants who responded at 48 hrs - drugs (N=6, 6, 6)	50.0 454.5%	0 0%	33.3 333%
% of participants who responded at 48 hrs - placebo (n=2,2,2)	0 0%	0 0%	50.0 500%
% of participants who responded at Day 43 - drugs (n=9,9,9)	55.6 505.5%	0 0%	44.4 444%
% of participants who responded at Day 43- placebo (n=3,3,3)	33.3 302.7%	0 0%	0 0%

Adverse Events

Time Frame	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.
Arm/Group Title	MIJ821 0.16 mg/kg Weekly*		MIJ821 0.16 mg/kg Every Other Week		MIJ821 0.32 mg/kg Weekly		MIJ821 0.32 mg/kg Every Other Week		Ketamine 0.5 mg/kg Weekly		Placebo Weekly		Total
Arm/Group Description	MIJ821 0.16 mg/kg weekly*		MIJ821 0.16 mg/kg every other week		MIJ821 0.32 mg/kg weekly		MIJ821 0.32 mg/kg every other week		Ketamine 0.5 mg/kg weekly		Placebo weekly		Total
All Cause Mortality
	MIJ821 0.16 mg/kg Weekly*		MIJ821 0.16 mg/kg Every Other Week		MIJ821 0.32 mg/kg Weekly		MIJ821 0.32 mg/kg Every Other Week		Ketamine 0.5 mg/kg Weekly		Placebo Weekly		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		0/70 (0%)
Serious Adverse Events
	MIJ821 0.16 mg/kg Weekly*		MIJ821 0.16 mg/kg Every Other Week		MIJ821 0.32 mg/kg Weekly		MIJ821 0.32 mg/kg Every Other Week		Ketamine 0.5 mg/kg Weekly		Placebo Weekly		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/11 (0%)		1/10 (10%)		0/10 (0%)		3/9 (33.3%)		0/10 (0%)		1/20 (5%)		5/70 (7.1%)
Cardiac disorders
Atrial fibrillation	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Psychiatric disorders
Major depression	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Suicide attempt	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		1/20 (5%)		1/70 (1.4%)
Suicide threat	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Other (Not Including Serious) Adverse Events
	MIJ821 0.16 mg/kg Weekly*		MIJ821 0.16 mg/kg Every Other Week		MIJ821 0.32 mg/kg Weekly		MIJ821 0.32 mg/kg Every Other Week		Ketamine 0.5 mg/kg Weekly		Placebo Weekly		Total
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/11 (63.6%)		6/10 (60%)		7/10 (70%)		6/9 (66.7%)		6/10 (60%)		5/20 (25%)		37/70 (52.9%)
Cardiac disorders
Angina pectoris	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Ear and labyrinth disorders
Hyperacusis	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		2/10 (20%)		0/20 (0%)		2/70 (2.9%)
Eye disorders
Asthenopia	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Photophobia	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Vision blurred	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Gastrointestinal disorders
Abdominal pain	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Dry mouth	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		3/10 (30%)		1/20 (5%)		4/70 (5.7%)
Dyspepsia	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Frequent bowel movements	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Nausea	0/11 (0%)		1/10 (10%)		1/10 (10%)		0/9 (0%)		2/10 (20%)		0/20 (0%)		4/70 (5.7%)
Vomiting	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
General disorders
Fatigue	0/11 (0%)		0/10 (0%)		2/10 (20%)		1/9 (11.1%)		1/10 (10%)		1/20 (5%)		5/70 (7.1%)
Feeling abnormal	3/11 (27.3%)		1/10 (10%)		2/10 (20%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		6/70 (8.6%)
Feeling of relaxation	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Gait disturbance	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Infections and infestations
Gastroenteritis	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Oral herpes	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Upper respiratory tract infection	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Urinary tract infection	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Injury, poisoning and procedural complications
Poisoning deliberate	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Investigations
Alanine aminotransferase increased	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Aspartate aminotransferase increased	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Blood potassium decreased	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Blood pressure increased	2/11 (18.2%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		3/70 (4.3%)
Blood pressure systolic increased	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Gamma-glutamyltransferase increased	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Platelet count decreased	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Metabolism and nutrition disorders
Hyponatraemia	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Musculoskeletal and connective tissue disorders
Back pain	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Nervous system disorders
Akathisia	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Amnesia	2/11 (18.2%)		0/10 (0%)		5/10 (50%)		3/9 (33.3%)		0/10 (0%)		0/20 (0%)		10/70 (14.3%)
Ataxia	0/11 (0%)		0/10 (0%)		1/10 (10%)		2/9 (22.2%)		0/10 (0%)		0/20 (0%)		3/70 (4.3%)
Disturbance in attention	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Dizziness	2/11 (18.2%)		3/10 (30%)		1/10 (10%)		1/9 (11.1%)		2/10 (20%)		1/20 (5%)		10/70 (14.3%)
Dysarthria	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Dysgeusia	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Headache	1/11 (9.1%)		0/10 (0%)		2/10 (20%)		1/9 (11.1%)		1/10 (10%)		1/20 (5%)		6/70 (8.6%)
Hypoaesthesia	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		1/20 (5%)		2/70 (2.9%)
Memory impairment	2/11 (18.2%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		3/70 (4.3%)
Paraesthesia	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		1/20 (5%)		3/70 (4.3%)
Sciatica	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Somnolence	2/11 (18.2%)		1/10 (10%)		4/10 (40%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		8/70 (11.4%)
Syncope	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Tunnel vision	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Psychiatric disorders
Abnormal dreams	0/11 (0%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Agitation	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Anxiety	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		1/10 (10%)		0/20 (0%)		2/70 (2.9%)
Confusional state	0/11 (0%)		0/10 (0%)		1/10 (10%)		1/9 (11.1%)		0/10 (0%)		1/20 (5%)		3/70 (4.3%)
Daydreaming	0/11 (0%)		0/10 (0%)		0/10 (0%)		1/9 (11.1%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Depersonalisation/derealisation disorder	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		5/10 (50%)		0/20 (0%)		5/70 (7.1%)
Disinhibition	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Dissociation	2/11 (18.2%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		1/20 (5%)		3/70 (4.3%)
Dissociative amnesia	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Euphoric mood	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Illusion	1/11 (9.1%)		1/10 (10%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		2/70 (2.9%)
Insomnia	2/11 (18.2%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		1/20 (5%)		3/70 (4.3%)
Irritability	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Mood swings	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Sleep disorder	1/11 (9.1%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Sleep terror	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Time perception altered	1/11 (9.1%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		2/70 (2.9%)
Skin and subcutaneous tissue disorders
Alopecia	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)
Hyperhidrosis	0/11 (0%)		0/10 (0%)		1/10 (10%)		0/9 (0%)		0/10 (0%)		0/20 (0%)		1/70 (1.4%)
Pruritus	0/11 (0%)		0/10 (0%)		0/10 (0%)		0/9 (0%)		1/10 (10%)		0/20 (0%)		1/70 (1.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.