Clinical trial NCT05454410
Conditions: Treatment-Resistant Depression
Keywords: Treatment-Resistant Depression Major Depressive Episode Major Depressive Disorder MIJ821 Anti-depressive Agent Subcutaneous Placebo Adult
Sponsor: Novartis Pharmaceuticals
Start date: 2023-03-13; Completion date: 2023-11-28
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study was to evaluate safety and efficacy of a single injection of MIJ821 in addition to standard of care (SoC) pharmacological anti-depressant treatment in participants with treatment-resistant depression (TRD)

Detailed description:
The trial included a screening period of up to 28 days. On Day 1, after screening, eligible participants were randomized to one of the treatment arms (1 mg, 4 mg, or 10 mg of MIJ821) or placebo and received study treatment administered as a single subcutaneous injection. Participants remained at the clinic for at least 4 hours after administration of study treatment for safety observation including assessment of local tolerability by visual inspection of the injection area. Post-dose clinic visits occurred 24 hours post dose (Day 2), Days 8, 15, 22 and 29 to evaluate efficacy and safety. Efficacy assessments included the Montgomery-Asberg Depression Scale (MADRS) and other clinical outcome assessments (COAs). Safety assessments included laboratory tests, ECGs, vital signs and physical examinations. In addition, phone calls were conducted 3 days after each on-site clinic visit with the exception of the End-of-study (EOS) visit. EOS visit was completed on site on Day 29. Including screening, participants were in the study for up to 8 weeks (57 days).

Arms: arm 1: Participants received a single dose of 1 mg MIJ821 administered as a subcutaneous (SC) injection on Day 1. arm 2: Participants received a single dose of 4 mg MIJ821 administered as an SC injection on Day 1. arm 3: Participants received a single dose of 10 mg MIJ821 administered as an SC injection on Day 1. arm 4: Participants received a single dose of 0.9% sodium chloride solution administered as an SC injection on Day 1.
Interventions: intervention 1: MIJ821 Subcutaneous Injection 1 mg intervention 2: MIJ821 Subcutaneous Injection 4 mg intervention 3: MIJ821 Subcutaneous Injection 10 mg intervention 4: Placebo Subcutaneous Injection
Intervention descriptions: intervention 1: MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1. intervention 2: MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1. intervention 3: MIJ821 supplied in vials as a powder for solution for injection, reconstituted and administered as a single SC injection on Day 1. intervention 4: 0.9% sodium chloride solution administered as a single SC injection on Day 1.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
MIJ821 
Clinical Trial Protocol CMIJ821B12201 / NCT05454410
A randomized, double-blind, placebo-controlled, parallel-
group trial to evaluate the efficacy, safety, tolerability, and 
pharmacokinetics of single subcutaneous MIJ821 injection 
in addition to standard of care in participants with 
treatment-resistant depression 
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2021-005992-38
Version number:
02 (Clean)
Clinical Trial Phase:
IIa
Release date: 
04-Nov-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 02 (04-Nov-2022) ......................................................................................... 13 
Amendment 01 (31-May-2022) ......................................................................................... 15 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 20 
1.1 
Background ............................................................................................................ 20 
1.1.1 
Treatment resistant depression .............................................................. 20 
1.1.2 
MIJ821 Preclinical summary ................................................................ 21 
1.1.3 
MIJ821 Clinical summary ..................................................................... 22 
1.2 
Purpose .................................................................................................................. 23 
2 
Objectives, endpoints and estimands ................................................................................. 23 
2.1 
Primary estimands ................................................................................................. 25 
2.2 
Secondary estimands ............................................................................................. 25 
3 
Study design ...................................................................................................................... 26 
4 
Rationale ............................................................................................................................ 29 
4.1 
Rationale for study design ..................................................................................... 29 
4.1.1 
Rationale for overall study design ......................................................... 29 
4.1.2 
Rationale for choice and timing of efficacy assessments ...................... 29 
4.1.3 
Rationale for safety assessments ........................................................... 30 
4.1.4 
Selection of patient population .............................................................. 30 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 30 
4.2.1 
Dose rationale ........................................................................................ 30 
4.2.2 
Rationale of treatment duration ............................................................. 31 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 32 
4.4 
Purpose and timing of interim analyses ................................................................. 32 
4.5 
Risks and benefits .................................................................................................. 33 
4.5.1 
Blood sample volume ............................................................................ 37 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 37 
5 
Study Population ............................................................................................................... 37 
5.1 
Inclusion criteria .................................................................................................... 38 
5.2 
Exclusion criteria ................................................................................................... 38 


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6 
Treatment ........................................................................................................................... 41 
6.1 
Study treatment ...................................................................................................... 41 
6.1.1 
Investigational and control drugs .......................................................... 41 
6.1.2 
Additional study treatments .................................................................. 41 
6.1.3 
Treatment arms/group ........................................................................... 41 
6.1.4 
Treatment duration ................................................................................ 42 
6.2 
Other treatment(s) .................................................................................................. 42 
6.2.1 
Concomitant therapy ............................................................................. 42 
6.2.2 
Prohibited medication ........................................................................... 43 
6.2.3 
Rescue medication ................................................................................ 45 
6.2.4 
Restriction for study participants .......................................................... 45 
6.3 
Preparation and dispensation ................................................................................. 46 
6.3.1 
Handling of study treatment and other treatment .................................. 46 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 47 
6.4 
Participant numbering, treatment assignment, randomization .............................. 47 
6.4.1 
Participant numbering ........................................................................... 47 
6.4.2 
Treatment assignment, randomization .................................................. 48 
6.5 
Treatment blinding ................................................................................................ 48 
6.6 
Dose escalation and dose modification.................................................................. 49 
6.7 
Additional treatment guidance ............................................................................... 49 
6.7.1 
Treatment compliance ........................................................................... 49 
6.7.2 
Recommended treatment of adverse events .......................................... 49 
6.7.3 
Emergency breaking of assigned treatment code .................................. 49 
7 
Informed consent procedures ............................................................................................ 50 
8 
Visit schedule and assessments ......................................................................................... 51 
8.1 
Screening ............................................................................................................... 57 
8.1.1 
Eligibility screening .............................................................................. 57 
8.1.2 
Information to be collected on screening failures ................................. 57 
8.2 
Participant demographics/other baseline characteristics ....................................... 58 
8.3 
Efficacy .................................................................................................................. 58 
8.3.1 
Handling of Efficacy Assessments by Independent Site Raters ........... 58 
8.3.2 
Montgomery Asberg Depression Rating Scale (MADRS), SIGMA 
version ................................................................................................... 59 
8.3.3 
Appropriateness of efficacy assessments .............................................. 59 
8.4 
Safety ..................................................................................................................... 59 
8.4.1 
Laboratory evaluations .......................................................................... 60 


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8.4.2 
Electrocardiogram (ECG) ..................................................................... 61 
8.4.3 
Pregnancy and assessments of fertility ................................................. 62 
8.4.4 
Safety evaluations related to mechanism of action of MIJ821 ............. 64 
8.4.5 
Oxygen saturation ................................................................................. 64 
8.4.6 
Appropriateness of safety measurements .............................................. 65 
8.5 
Additional assessments .......................................................................................... 65 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 65 
8.5.2 
Pharmacokinetics .................................................................................. 68 
 
 68 
8.5.4 
Other Assessments ................................................................................ 69 
9 
Discontinuation and completion ........................................................................................ 70 
9.1 
Discontinuation from study treatment and from study .......................................... 70 
9.1.1 
Discontinuation from study treatment ................................................... 70 
9.1.2 
Discontinuation from study ................................................................... 70 
9.1.3 
Lost to follow-up ................................................................................... 70 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 70 
9.3 
Study stopping rules .............................................................................................. 71 
9.4 
Study completion and post-study treatment .......................................................... 71 
9.5 
Early study termination by the sponsor ................................................................. 71 
10 Safety monitoring, reporting and committees ................................................................... 72 
10.1 
Definition of adverse events and reporting requirements ...................................... 72 
10.1.1 
Adverse events ...................................................................................... 72 
10.1.2 
Serious adverse events .......................................................................... 74 
10.1.3 
SAE reporting........................................................................................ 75 
10.1.4 
Pregnancy reporting .............................................................................. 76 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 76 
10.2 
Additional Safety Monitoring ................................................................................ 77 
10.2.1 
Liver safety monitoring ......................................................................... 77 
10.2.2 
Renal safety monitoring ........................................................................ 78 
10.2.3 
Cardiac Monitoring ............................................................................... 78 
10.2.4 
Prospective suicidality assessment ........................................................ 79 
10.2.5 
Adverse events of special interest ......................................................... 80 
10.3 
Committees ............................................................................................................ 81 
10.3.1 
Data Monitoring Committee ................................................................. 81 
10.3.2 
Steering Committee ............................................................................... 81 
11 Data Collection and Database management ...................................................................... 82 


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11.1 
Data collection ....................................................................................................... 82 
11.2 
Database management and quality control ............................................................ 82 
11.3 
Site monitoring ...................................................................................................... 83 
12 Data analysis and statistical methods ................................................................................ 84 
12.1 
Analysis sets .......................................................................................................... 84 
12.2 
Participant demographics and other baseline characteristics ................................. 84 
12.3 
Treatments ............................................................................................................. 84 
12.4 
Analysis supporting primary objectives ................................................................ 85 
12.4.1 
Definition of primary endpoint(s) ......................................................... 85 
 
 86 
 
 88 
12.4.4 
Handling of missing values not related to intercurrent event ............... 88 
 
 88 
 
 88 
12.5 
Analysis supporting secondary objectives ............................................................. 89 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 89 
12.5.2 
Safety endpoints .................................................................................... 89 
12.5.3 
Pharmacokinetics .................................................................................. 90 
 
 91 
 
 91 
12.5.6 
PK/PD relationships .............................................................................. 92 
 
 92 
 
 92 
 
 92 
12.7 
Interim analyses ..................................................................................................... 92 
12.8 
Sample size calculation.......................................................................................... 93 
12.8.1 
Primary endpoint(s) ............................................................................... 93 
12.8.2 
Secondary endpoint(s) ........................................................................... 93 
13 Ethical considerations and administrative procedures ...................................................... 93 
13.1 
Regulatory and ethical compliance ........................................................................ 93 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 93 
13.3 
Publication of study protocol and results............................................................... 93 
13.4 
Quality Control and Quality Assurance ................................................................. 94 
13.5 
Participant Engagement ......................................................................................... 94 
14 Protocol adherence ............................................................................................................ 94 
14.1 
Protocol amendments............................................................................................. 95 


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15 References ......................................................................................................................... 96 
16 Appendices ........................................................................................................................ 98 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs ......................... 98 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 98 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event Follow-up .... 100 
16.4 
Appendix 4: ECG Alert Threshold Values .......................................................... 101 
16.5 
Appendix 5: Medications with a Known Risk of Torsades de Pointes ............... 101 
16.6 
Appendix 6: Antidepressants recommended to be used as background therapy 
during the study ................................................................................................... 103 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 23 
Table 4-1 
Risks associated with MIJ821 ............................................................... 33 
Table 6-1 
Investigational and control drug ............................................................ 41 
Table 6-2 
Prohibited Medications or Treatment.................................................... 44 
Table 8-1 
Assessment Schedule ............................................................................ 53 
Table 8-2 
Assessment Specification ...................................................................... 59 
Table 8-3 
Clinical laboratory parameters collection plan ..................................... 61 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 77 
Table 12-1 
Potential intercurrent events, estimand strategy and data handling ...... 88 
Table 12-2 
Non-compartmental pharmacokinetic parameters ................................ 91 
Table 16-1 
16-1 Clinically notable values for vital signs ........................................ 98 
Table 16-2 
Liver event and laboratory trigger definitions ...................................... 98 
Table 16-3 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 98 
Table 16-4 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 99 
Table 16-5 
Specific Renal Alert Criteria and Actions ........................................... 100 
Table 16-6 
Follow-up of renal events .................................................................... 101 
Table 16-7 
Medications with a Known Risk* of Torsades de Pointes .................. 101 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 26 
Figure 8-1 
Timing of study procedures .................................................................. 61 
 
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List of abbreviations 
ACR 
Albumin-Creatinine Ratio 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
APA 
American Psychiatric Association  
APTT 
Activated partial thromboplastin time  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
AUCinf 
Area Under the Curve from time zero to infinity 
AUClast 
Area under the curve from time zero to time of last measurable concentration 
AV 
atrioventricular 
BDI-II 
Beck Depression Inventory II  
BMI 
Body Mass Index 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CADSS 
Clinical-Administered Dissociative States Scale 
CK 
creatinine kinase 
ClinRO 
Clinician Reported Outcomes 
cm 
centimeters 
Cmax 
maximum plasma drug concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CNS 
Central Nervous System 
COA 
Clinical Outcome Assessment 
COVID-19 
Coronavirus Disease 
CQA 
Clinical Quality Assurance 
CR 
concentration-response 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
 
 
DBP 
Diastolic Blood Pressure 
DBS 
Deep brain stimulation  
DDE 
direct data entry 
DDI 
drug-drug interaction 
DIN 
Drug Inducted Nephrotoxicity 
DR 
Dose Response 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 


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EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECT 
Electroconvulsive therapy  
ED50 
the dose at which half of the maximum effect is reached 
EDC 
Electronic Data Capture 
EFD 
Embryo-fetal development  
EMA 
European Medicines Agency 
EOS 
End-of-study 
eSAE 
Electronic Serious Adverse Event 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FIH 
First in Human 
FSH 
Follicle Stimulating Hormone 
fT3 
free triiodothyronine  
fT4 
free thyroxine  
FWER 
Family-Wise Error Rate 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GLP 
Good Laboratory Practices 
HBcAg 
Hepatitis B core antigen 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HDL 
High Density Lipoprotein 
hERG 
human Ether-à-go-go-Related Gene 
HIV 
Human immunodeficiency virus 
HV 
healthy volunteer 
I.E. 
Intercurrent Event 
i.v. 
intravenous 
IB 
Investigator's Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
kg 
kilogram(s) 
LDH 
lactate dehydrogenase 
LDL 
Low Density Lipoprotein 
LFT 
Liver function test  


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LLOQ 
lower limit of quantification 
LoE 
Lack of Efficacy 
MADRS 
Montgomery Asberg Depression Scale 
MAOI 
Monoamine oxidase inhibitors 
MCP 
Multiple Comparison Procedures 
 
  
MDD 
Major Depressive Disorder 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
MGH-ATRQ 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
mL 
milliliter(s) 
MMDC 
Melancholia and Mixed Depression Diagnostic 
mmHg 
millimetre of mercury 
MMRM 
Mixed-effects Model for Repeated Measures 
MoA 
mechanism of action 
MOAA/S 
Modified Observer's Assessment of Alertness and Sedation 
msec 
millisecond 
MTD 
Maximum Tolerated Dose 
NAM 
negative allosteric modulator  
ng 
nanogram(s) 
NMDA 
N-methyl-D-aspartate 
NMDAR 
N-methyl-D-aspartate receptor 
NOAEL 
no observed adverse effect level  
PCR 
Protein-Creatinine Ratio 
PD 
Pharmacodynamic(s) 
PE 
physical examination 
PK 
Pharmacokinetic(s) 
PoC 
Proof of Concept 
 
 
PT 
prothrombin time 
PT/INR 
Prothrombin time/International normalized ratio  
QTcF 
QT interval corrected by Fridericia’s formula 
RNA 
Ribonucleic Acid 
RO 
receptor occupancy  
SCID-5 
Structured Clinical Interview for DSM-V Disorders 
S-STS 
Sheehan-Suicidality Tracking Scale  
s.c. 
subcutaneous 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-
2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic Blood Pressure 
SD 
standard deviation 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 


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SIGMA 
Structured Interview Guide for MADRS 
SNRI 
Selective Norepinephrine Reuptake Inhibitors 
SPRAVATO 
esketamine 
SSRI 
Selective Serotonin Reuptake Inhibitors 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Elimination half-life 
TBIL 
Total Bilirubin 
TdP 
Torsades de Pointes  
TEAE 
Treatment-emergent adverse event 
Tmax 
time to reach maximum plasma concentration 
TMS 
Transcranial magnetic stimulation 
TRD 
Treatment-Resistant Depression 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
UTI 
Urinary Tract Infection 
VNS 
Vagus nerve stimulation  
WBC 
white blood cell 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 
WOCBP 
Women of child bearing potential 
μM 
micromolar 
 
 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (IMP) (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or characteristic, or a 
group of individuals followed-up or traced over time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Discontinuation 
from study 
Point/time when the participant permanently stops further protocol required 
assessments or follow-up, for any reason. No specific request is made to stop the use 
of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 milligrams 
(mg) once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant  
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to sponsors and other oversight authorities, as 
appropriate 
Estimand  
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same participants 
under different treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well as the 
specification of how the remaining intercurrent events are addressed and a population-
level summary for the variable. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study or the participant allocated to an invalid stratification factor 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy) 




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Amendment 02 (04-Nov-2022) 
 
Amendment rationale 
The purpose of this protocol amendment is to replace the Mini International Neuropsychiatric 
Interview (M.I.N.I), used at screening to assess whether the diagnostic criteria have been met, 
by an equivalent validated instrument: the Structured Clinical Interview for DSM-V Disorders 
(SCID-5). The M.I.N.I cannot be used in this trial due to difficulties related to copyright license 
agreement's activities, which cannot be overcome in timely manner.  
In order to ensure the appropriate patient population is enrolled in this study, the SCID-5 will 
be used at screening. The SCID-5 is a widely used structured diagnostic instrument for assessing 
DSM-5 disorders which was also used in the Proof-of-Concept (CMIJ821X2201) study in 
participants with Treatment Resistant Depression (TRD).  
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  
The changes being made to the protocol due to this amendment are incorporated in the following 
sections: 
• The M.I.N.I was replaced by the SCID-5 in the List of Abbreviations, the Protocol 
summary, in sections 5.1 Inclusion Criteria, 5.2 Exclusion Criteria, 8.5.1.1 Clinical 
Reported Outcomes (ClinRO) and in Table 8-1 Assessment Schedule. 
• As per exclusion criterion 1, patients who received brain stimulation procedures within 
one year prior to screening are excluded. Transcranial magnetic stimulation (TMS) has 
now been added to exclusion criterion 1, section 5.2 Exclusion criteria, as the procedure 
is currently widely used in some participating countries/clinical sites and the related 
exclusionary period for brain procedures has been further specified. 
 
Some inconsistencies have also been addressed in the following sections: 
• Section 8.5.1.1 Clinician Reported Outcomes (ClinRO) 
It has been clarified that the Massachusetts General Hospital Antidepressant Treatment 
Response Questionnaire (MGH-ATRQ) is designed to capture all treatments (failed 
and successful) used in the current episode, only. 
• Section 9.1.3 Lost to follow-up, Section 10.2.1 Liver Safety Monitoring and Section 
10.2.3 Cardiac Monitoring 
Any reference to treatment interruption was removed as this is a single dose study. 
 
In addition to the above, correction of broken hyperlinks, minor typographical and formatting 
errors has been made where needed. 
 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are substantial and require IRB/IEC approval 
prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Amendment 01 (31-May-2022) 
 
Amendment rationale 
The purpose of this protocol amendment is to clarify that the End of-Study (EoS) visit (Day 29) 
is the last study visit for ensuring safety follow-up and thus a safety follow-up call at Day 31 is 
not required while taking into consideration the pharmacokinetic profile of MIJ821 (five half-
lives of MIJ821). The protocol has the provision to ensure that any related serious adverse 
events carry on being reported beyond EoS visit unless otherwise specified by local 
law/regulations. 
Furthermore, the protocol is amended to clarify that in case of extended safety monitoring for 
adverse events on Day 1, between 4 hours and 24 hours post-dose, additional safety tests or 
measures may be required including but not limited to unscheduled pharmacokinetic (PK) 
samples.  
The recall periods for the Montgomery Asberg Depression Rating Scale (MADRS) 
 
 have been added in order to adequately 
assess efficacy at the 4 hour-time point on Day 1. In addition the recall period of the MADRS 
used at screening has been specified: “Last 7 days with euthymic baseline”. The recall period 
of the Clinician-Administered Dissociative States Scale (CADSS) has also been added. The 
recall period of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the first study visit 
has been updated to reflect that this version assesses suicidal ideation and suicidal behavior 
during the participant's last one year and during a predefined period of one month. 
Minor inconsistencies have been addressed in this amendment, and clarifications added where 
needed. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.  
The changes being made to the protocol due to this amendment are incorporated in the following 
sections: 
• Protocol Summary  
Section updated for consistency with the main body of the protocol. 
• Section 2 Objectives, endpoints and estimands 
The endpoint related to the assessment of the efficacy of MIJ821 on measures of response 
and remission was updated with the required study days.  
• Section 3 Study Design  
Section updated to define End of Study Visit (EoS) as Day 29.  
• Section 5.1 Inclusion criteria  
Inclusion criteria 6 wording updated in order to align with protocol text in Section 6.2.1 
and Appendix 6 (Antidepressants recommended to be used as background therapy during 
the study). 


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• Section 6.4.2 Treatment assignment, randomization 
It has been clarified that the randomization will be stratified by class of current anti-
depressant standard of care (Selective Norepinephrine Reuptake Inhibitors (SNRI), 
Selective Serotonin Reuptake Inhibitors (SSRI) or other anti-depressants or combination 
of anti-depressants). 
• Table 8.1 Assessment Schedule  
Table updated to specify the assessments to be recorded on source documentation only.  
In addition, Day 31 visit was removed and EoS defined as Day 29. Updates to Section 9 
and Section 10 have been made to align with this change. 
• Section 8.2 Participant demographics/other baseline characteristics  
Section updated to include the collection of participants’ socio-economical and baseline 
disease characteristic data. This data is part of psychiatric standard of care data collected 
to characterize the patient’s current condition. 
• Section 8.3.2 Montgomery Asberg Depression Rating Scale (MADRS), SIGMA version 
 Sections updated to include the recall period at baseline and at 4 hour on Day 1.  
•  Section 8.5.1.1 Clinician Reported Outcomes (ClinRO)  
Sections updated to include a recall period at 4 hour on Day 1 for MADRS 
 (to 
adequately assess efficacy at the 4 hour-timepoint on Day 1) and to update the recall 
period for C-SSRS at the first study visit. 
• Section 8.4.4.1 Clinician-Administered Dissociative States Scale (CADSS) 
 The recall period used is “current”. 
• Section 8.4.4.3 Memory Assessment using orientation questions 
Section updated to clarify that the outcome of this assessment is only captured in the 
eCRF if amnesia is considered as an AE.  
• Section 8.5.2 Pharmacokinetics 
Section updated to clarify that additional PK samples may be collected in case of 
unscheduled visits for safety monitoring purposes during the time-period from 4 hours to 
24 hours post-dose. 
• Section 10.2.4 Prospective suicidality assessment 
Section updated to clarify that the “baseline/screening” version of the C-SSRS at the first 
study visit assesses suicidal ideation and suicidal behavior during the participant's last one 
year and during a predefined period of one month. 
• Section 16.6. Appendix 6.  
The title of the appendix was missing and has been added. In addition, the table was 
updated with medications that are prohibited only within a time-window before and after 
study drug injection but can be used as background therapy during the trial. Clarification 
added in the footer. 
 
In addition to the above, correction of minor typographical errors and clarifications have been 
made where needed. 
 
 
 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are substantial and require IRB/IEC approval 
prior to implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
CMIJ821B12201 
Full Title 
A randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the 
efficacy, safety, tolerability, and pharmacokinetics of single subcutaneous MIJ821 
injection in addition to standard of care in participants with treatment-resistant 
depression 
Brief title 
Study of efficacy, safety, tolerability and pharmacokinetics of MIJ821 in participants with 
treatment- resistant depression (TRD) 
Sponsor and 
Clinical Phase 
Novartis 
Phase IIa 
Investigation type 
Drug  
Study type 
Interventional 
Purpose 
The main purpose of this non-confirmatory study is to evaluate the clinical responses of 
MIJ821 in participants suffering from TRD treated with a single subcutaneous (s.c.) 
MIJ821 injection. Furthermore, it is expected that this study will guide the dose selection 
for future clinical trials with MIJ821 in TRD. 
Primary 
Objective(s)  
To assess efficacy of MIJ821 (versus placebo) in TRD after single s.c. injection. The 
primary clinical question of interest is: What is the effect of MIJ821 (versus placebo) on 
change in Montgomery Asberg Depression Rating scale (MADRS) total score 24 hours 
after single s.c. injection compared to baseline assessment in participants with TRD 
who have already failed to adequately respond to at least two conventional 
antidepressants. 
Secondary 
Objectives 
To assess safety and tolerability of MIJ821 after single s.c. injection  
To assess MIJ821 pharmacokinetics (PK) in plasma after single s.c. injection 
To assess the duration of antidepressant effect of MIJ821 
To characterize the dose-response and exposure-response relationship of MIJ821 
Study design 
This is a non-confirmatory, randomized, double-blind, placebo controlled, parallel-group 
trial. The study will enroll approximately 56 participants presenting with TRD. The study 
consists of a screening period (D-28 to D1), a treatment period (D1) and a 4-week 
follow-up period with an end of study (EOS) visit on Day 29. The maximum duration of 
the study, including screening, is approximately 8 weeks. 
Rationale 
This study will support the dose selection and dose regimen for future Phase 3 clinical 
trials by evaluating efficacy and safety of 3 doses of MIJ821 (1mg, 4mg and 10mg) 
administered subcutaneously, on top of pharmacological antidepressant standard of 
care (SoC) treatment in participants with TRD. 
 
Study population 
Male and female participants, 18 to 65 years (inclusive), diagnosed with TRD.  
Key Inclusion 
criteria 
● Signed informed consent must be obtained prior to participation in the study 
● Male and female participants,18 to 65 years of age (inclusive) at screening 
● Participant has a diagnosis of recurrent major depressive disorder (MDD) and a 
current major depressive episode of at least 8 weeks in duration as defined by 
Diagnostic and Statistical Manual of Mental Disorders, Firth Edition (DSM-5) criteria and 
confirmed by both SCID-5 and adequate clinical psychiatric evaluation at Screening 
● Participant obtains a MADRS score ≥ 24 at screening and before randomization on 
Day 1 
● Failure to respond to 2 or more prior antidepressant treatments but not more than 5, 
where two failed treatments are of two different antidepressants, with adequate dose 
and duration (≥ 6 weeks duration, doses defined per agent), as identified by the 
Massachusetts General Hospital Antidepressant Treatment Response Questionnaire 
(MGH-ATRQ), based on patient's report and prior psychiatric history, assessed by the 
investigator, and further documented by medical records. Patients with historical 
treatment failure to esketamine, ketamine or arketamine are excluded 
Key Exclusion 
criteria 
● Any prior or current diagnosis of MDD with psychotic features, bipolar disorder, 
schizophrenia, or schizoaffective disorder as obtained from SCID-5 at Screening  
● Current acute depressive episode lasting longer than two years continuously, or 
participants receiving electroconvulsive therapy (ECT), transcranial magnetic 




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1 
Introduction 
1.1 
Background 
1.1.1 
Treatment resistant depression 
Depression is a serious and life-threatening condition with high rates of morbidity and a chronic 
disease course. It is a common illness worldwide, with more than 264 million people affected 
(WHO 2020). When long-lasting and with moderate or severe intensity, depression causes the 
affected person to suffer greatly, impairing the ability to work, self-care, and maintain 
relationships.  
Despite a broad availability of antidepressant medication, about a third of patients suffering 
from MDD fail to respond fully to antidepressant treatment of adequate duration and dose, and 
the majority fail to maintain long-term response to standard antidepressants (Rush et al 2006). 
This chronicity of symptoms predisposes patients to treatment resistance. 
Treatment-resistant depression (TRD) is defined as a lack of clinically meaningful improvement 
after treatment with at least 2 different antidepressant agents prescribed in adequate dosages for 
adequate durations. 
Patients suffering from TRD are very likely to have suicidal ideation and experience a 
disproportionate burden of illness causing significant impairment and increased morbidity 
(Shelton et al 2010).  
Therefore, there is a high unmet medical need for rapid-acting antidepressants that are either 
more effective or better tolerated, treatments that can effectively interrupt a depressive episode 
and are able to prevent future depressive episodes. 
Ketamine, which is a N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to 
be effective in TRD in off-label research, but is limited by psychotomimetic side effects 
(Katalinic et al 2013, Browne and Lucki 2013). Further, ketamine has been shown to be rapid-
acting and reduce suicidality (Katalinic et al 2013). The efficacy of ketamine provides the 
rationale for targeting N-methyl-D-aspartate (NMDA) receptor inhibition as a rapid-onset 
antidepressant mechanism.  
SPRAVATO® (esketamine), a non-competitive NMDA receptor antagonist, is approved for the 
treatment of TRD and is also approved for MDD with acute suicidal ideation or behavior by the 
Food and Drug Administration (FDA) and for moderate to severe episode of MDD as acute 
short-term treatment in conjunction with an oral antidepressant for the rapid reduction of 
symptoms which according to clinical judgement constitute a psychiatric emergency by the 
European Medicines Agency (EMA]). While both ketamine and SPRAVATO have 
demonstrated a certain level of efficacy and showed rapid mode of action, their safety profiles 
are not without adverse effects meaningful both for patients and clinicians. 
Targeting a specific subset of NMDA receptors is one approach to potentially mitigate adverse 
effects of NMDA receptor inhibition while retaining the antidepressant efficacy. Preskorn 
(Preskorn et al 2008) demonstrated that infusion of traxoprodil, a negative allosteric modulator 
selective for the NR2B subtype of NMDA receptors, also known as CP-101,606, was 
efficacious in TRD patients with the magnitude and duration of response comparable to those 


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of ketamine with low potential to produce dissociative effects in patients. Ibrahim et al 
(Ibrahim et al 2012) reported that MK-0657 (Rislenemdaz, a selective NR2B antagonist) did 
not induce dissociative effects in TRD patients and was generally safe. Taken together, this 
suggest that achieving safe, yet rapid-onset antidepressant efficacy is feasible with a compound 
selectively inhibiting NR2B receptor. 
1.1.2 
MIJ821 Preclinical summary 
MIJ821 is a highly potent, selective and reversible low molecular weight negative allosteric 
modulator (NAM) targeting the NR2B sub-unit of the N-methyl-D-aspartate receptors 
(NMDARs). 
The primary pharmacological properties of MIJ821 were characterized in vitro and in vivo and 
established a pharmacological basis for the intended clinical use. Non-clinical drug disposition 
and exposure effect were assessed. In vivo, MIJ821 was shown to distribute into the rat brain. 
The non-clinical safety profile of MIJ821 was evaluated in rats and dogs using the intravenous 
(i.v.) bolus route in studies of up to 6 weeks in duration. The choice of rats and dogs as 
preclinical species is justified by the relevance of these species in terms of pharmacology and 
metabolism. Key findings were as follows: 
• While MIJ821 shows some in vitro off-target activity below 1 micromolar (μM), the risk 
of off-target pharmacology at therapeutically relevant exposures is considered low. 
• In safety pharmacology, MIJ821-related findings included cardiovascular effects (human 
Ether-à-go-go-Related Gene (hERG) channel potassium current inhibition half maximal 
inhibitory concentration (IC50) = 1.1 µM; increased heart rate in dogs) and, in rats, lack of 
pinna response and increased respiration rate. 
• In pivotal 6-week Good Laboratory Practice (GLP) studies, MIJ821 given i.v. twice a 
week was tolerated with no adverse effects and the top dose of 10 mg/kg was defined as 
the no observed adverse effect level (NOAEL) in rats and dogs. The main targets 
identified included the Central Nervous System (CNS) (clinical signs assumed to represent 
exaggerated pharmacological effects) and the cardiovascular system (as seen in safety 
pharmacology). There were no MIJ821-related local findings at the i.v. infusion or 
subcutaneous (s.c.) injection sites. 
• MIJ821 did not induce neuronal vacuolation or necrosis. 
• MIJ821 is not genotoxic or phototoxic. 
• Embryo-fetal development (EFD) studies in rats and rabbits (daily i.v. administration 
during gestation) showed that MIJ821 is not teratogenic. In rats, MIJ821 was well 
tolerated. In rabbits, doses ≥ 9 mg/kg/day were above the maximal tolerated dose (MTD) 
for maternal animals and caused embryo lethality. 
• NOAELs were identified in all pivotal studies with safety margins adequate for the 
pursued indication. 
Further details are provided in the Investigator's Brochure (IB). 


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1.1.3 
MIJ821 Clinical summary 
The MIJ821 clinical development program aims to evaluate MIJ821 as a short-term, fast-acting 
treatment for adult participants with MDD who have acute suicidal ideation and behavior (initial 
indication) and as a treatment of adult participants with TRD (follow-on indication). 
MIJ821 has been studied in a Phase 1 First-In-Human study (FIH, CMIJ821X2101) in healthy 
volunteers (HV) and in a Phase 2a Proof-of-Concept (PoC CMIJ821X2201) clinical study in 
participants with TRD after i.v. administration. A Phase 1 study is also ongoing to investigate 
the safety, tolerability and pharmacokinetic (PK) of subcutaneous MIJ821 in HVs 
(CMIJ821A02101). 
First-In-Human study (CMIJ821X2101) 
In a FIH study, MIJ821 was intravenously administered at single ascending doses (SAD) of 
0.016, 0.048, 0.16, 0.24, 0.32, and 0.48 mg/kg (Part 1) and at repeated doses of 0.32 mg/kg 
given one week apart (Part 2) to HVs. Dissociative AEs, amnesia and sedation were observed 
at doses higher than 0.16 mg/kg. 
In term of pharmacokinetics, no obvious PK difference has been identified between the two 
dosing events in the repeated dose part of the study. 
PoC study in TRD participants (CMIJ821X2201) 
This PoC study evaluated the safety and efficacy responses to MIJ821 in participants suffering 
from TRD (defined as failing two or more prior antidepressants, one in the current episode) 
assessed by the MADRS, a validated and widely employed method in depression trials (see 
details in Section 8.3.1). Participants were randomized with a ratio of 3:3:3:3:6:4 to one of six 
treatment arms: i) MIJ821 0.16 mg/kg one infusion per week (weekly), ii) MIJ821 0.16 mg/kg 
one infusion every other week (biweekly), iii) MIJ821 0.32 mg/kg weekly, iv) MIJ821 0.32 
mg/kg biweekly, v) placebo weekly, and vi) ketamine 0.5 mg/kg weekly. 
A total of 72 participants were randomized: 41 on MIJ821 across the 4 MIJ821 arms, 11 on 
ketamine and 20 on placebo. Out of these 72 participants randomized, 70 received study drug 
and were included in both efficacy and safety analyses. Two participants were randomized but 
did not receive study drug: 1 patient in MIJ821 0.32 mg/kg biweekly arm for physician decision 
and 1 patient in ketamine arm for adverse event before treatment. Overall, 53 (75.7%) 
completed the treatment and 50 (71.4%) completed the follow-up period. The most common 
reason for treatment discontinuation was participant/guardian decision (15.7%). 
The primary endpoint of the study was the change from baseline in the total MADRS score at 
24 hours after the start of the infusion compared to placebo. Both the MIJ821 0.16 mg/kg and 
the 0.32 mg/kg doses (pooled across weekly and bi-weekly dosing regimens) were superior to 
placebo on the primary endpoint. The MADRS adjusted arithmetic mean difference vs. placebo 
was −8.25 points (p=0.0013) for the pooled 0.16 mg/kg group and −5.71 points (p=0.0196) for 
the pooled 0.32 mg/kg group.  
The safety and tolerability profile of MIJ821 was generally favorable across all the dosing 
regimens. The overall incidence of AEs was similar across the MIJ821 dose groups (61.9% for 
pooled 0.16 mg/kg and 68.4% for pooled 0.32 mg/kg) and the ketamine group (60.0%), which 


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were all higher than in the placebo group (35.0%). The most commonly reported AEs were 
amnesia (overall incidence across treatment groups: 14.3%), dizziness (14.3%), somnolence 
(11.4%), feeling abnormal (8.6%), headache (8.6%), depersonalization/derealization disorder 
(7.1%), fatigue (7.1%), dry mouth (5.7%) and nausea (5.7%). 
Phase 1 study in HVs with s.c. MIJ821 (CMIJ821A02101) 
This is a SAD study with randomized, participant and investigator blinded, placebo controlled 
design to investigate the safety, tolerability and PK of s.c. administered MIJ821 in healthy 
participants. The study is ongoing and will include approximately 32 non-Japanese and 12 
Japanese participants. Study participants (non-Japanese) have already been enrolled into three 
sequential cohorts and received a single s.c. dose of 1, 4 or 12 mg MIJ821 or placebo. Eight 
participants completed treatment in each cohort with a randomization ratio 3:1 for MIJ821 to 
placebo. Subsequently, 12 Japanese participants will be enrolled into a single cohort and receive 
a dose of s.c. MIJ821 or placebo. The exact dose of MIJ821 in the Japanese cohort will be 
determined based on the results of the cohorts with non-Japanese participants. 
Preliminary blinded data with s.c. MIJ821 are available from the ongoing double blind, placebo 
controlled SAD study (CMIJ821A02101). In this study, dissociative AEs were reported in the 
4 and 12 mg cohorts, where MIJ821 exposure was comparable to that reached by 0.048 and 
0.16 mg/kg i.v. doses in the FIH study, respectively. All of these events were mild or moderate 
in severity and resolved without treatment. 
1.2 
Purpose 
The main purpose of this non-confirmatory study is to evaluate the safety and efficacy of a 
single s.c. MIJ821 injection in addition to standard pharmacological antidepressant (SoC) 
treatment 
in 
participants 
suffering 
from 
TRD 
assessed 
by 
the 
MADRS 
(Montgomery and Asberg 1979), a validated and widely employed scale in depression trials, 
evaluated 24h after study drug administration.  
Furthermore, it is expected that this study will provide information about the dose-response and 
exposure-response relationship of the antidepressant effect of MIJ821 after single s.c. injection, 
which will be used to guide dose selection for confirmatory studies. 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To assess efficacy of MIJ821 (versus placebo) in 
treatment resistant depression after single s.c. 
injection 
● MADRS total score at 24 hours after s.c. injection 
compared to baseline assessment 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To assess safety and tolerability of MIJ821 after 
single s.c. injection 
● Incidence and severity of treatment-emergent 
adverse events (TEAEs), including AEs of special 
interest; standard safety assessments such as vital 
signs, ECG, hematology, blood chemistry, urinalysis; 
Clinician-Administered Dissociative States Scale 


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Objective(s) 
Endpoint(s) 
(CADSS) score, Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S), C-SSRS, memory 
assessment using orientation questions, results of 
local tolerability assessments 
● To assess MIJ821 PK in plasma after single s.c. 
injection 
● PK properties of MIJ821 in plasma described by 
Area under the curve from time zero to time of last 
measurable concentration (AUClast), maximum 
plasma drug concentration (Cmax), time to reach 
maximum plasma concentration (Tmax) (parameters 
not limited). 
● To assess the duration of antidepressant effect of 
MIJ821 
● MADRS total score at Day 8, 15, 22 and 29 visits 
compared to baseline 
● To characterize the dose-response and exposure-
response relationship of MIJ821 
● Dose-response relationship of MIJ821 with respect 
to change from baseline in MADRS total score at 24 
hours after single s.c. injection 
● Exposure-response relationship of MIJ821 with 
respect to change from baseline in MADRS total 
score at 24 hours (Day 2)  


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2.1 
Primary estimands 
The primary clinical question of interest is: What is the effect of s.c. MIJ821 (versus placebo) 
given in addition to standard pharmacological antidepressant (SoC) treatment 24 hours after the 
injection of the study drug on change in depressive symptoms in participants with TRD, who 
have already failed to adequately respond to at least two conventional antidepressants.  
Rationale 
The justification for the primary estimand is that it will allow to estimate the rapid effect of the 
study drug in a population of depressed participants, who are considered treatment resistant, 
based on the definition above. A rapid response is clinically valuable as conventional 
antidepressants might need several weeks to achieve reduction of depressive symptoms. 
The primary estimand is described by the following attributes: 
1. Population: participants with treatment resistant depression, who have failed to show 
adequate treatment response to at least 2 antidepressants previously. 
2. Primary variable: change from baseline to 24 hours post dose in the MADRS total score. 
3. Treatment of interest: the randomized treatment (the investigational treatment MIJ821 or 
the placebo treatment) administered as a single s.c. injection on Day 1. The dose of the 
allowed concomitant medication (i.e., SoC) for depression must remain stable during the 
trial. 
4. Handling of intercurrent events (IEs) prior to MADRS assessment at 24 hours (for more 
details see Section 12.4.3): 
• New intake or change in concomitant medications/therapies which have a potential 
confounding effect: hypothetical strategy 
• Intake of prohibited medications: hypothetical strategy 
• Intake of rescue medications: hypothetical strategy 
• IEs related to pandemic: hypothetical strategy 
• IEs leading to study discontinuation due to adverse (AEs), lack of efficacy or other 
reasons: treatment policy 
Participants who took prohibited medications, rescue medications, or took new or change 
concomitant therapy which have potential confounding effect, will continue in the study and be 
assessed as scheduled. 
Further details about the concomitant therapy, prohibited and rescue medications are provided 
in Section 6.2. 
The summary measure: difference in variable means between study drug and placebo. 
The Multiple Comparisons Procedures - Modeling (MCP-Mod) approach will be used to assess 
the primary objective (for more details on this approach see Section 12.4.2). 
2.2 
Secondary estimands 
Not applicable 




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include physical examinations (PEs), ECGs, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, and urinalysis), administration of the CADSS, MOAA/S, C-
SSRS, and memory assessment using orientation questions. Local tolerability will be evaluated 
by visual inspection of the injection area. Injection site abnormalities reaching the threshold of 
mild changes will also be assessed quantitatively (refer to Section 8.5.4). 
Participants will be allowed to leave the clinical site at the earliest 4 hours after dosing, if all of 
the following criteria are fulfilled: 
• The participant does neither report nor present with any CNS adverse events (dissociation, 
amnesia, sedation) 
• There is no increase in suicidal intensity or new occurrence of suicidal ideation as 
assessed by C-SSRS 
• No clinically relevant QTcF prolongation (QTcF≥500 msec or increase in QTcF from 
baseline≥60 msec) 
• No clinically relevant abnormalities in blood pressure (BP) (90≤Sysotlic BP (SBP) ≥180 
mmHg or 50≤Diastolic BP (DBP) ≥105 mmHg or increase or decrease in SBP of at least 
20 mmHg or increase or decrease in DBP of at least 15 mmHg from baseline) or any 
increase in BP that is accompanied by symptoms, such as headache, dizziness, nausea, 
visual disturbances or other neurological symptoms 
• The investigator does not identify any other AEs that require continued monitoring 
If the participant cannot be released from the clinical site 4 hours after dosing, extended safety 
monitoring will be performed as described below.  
The post-dose follow-up period will continue for 4 weeks (28 days) after treatment. On-site 
visits to assess efficacy and safety are scheduled on Day 2 (24 hours post-dose) and 
subsequently every week (i.e., on Days 8, 15, 22 and 29) during the follow-up period. The 
assessment to address the primary objective will be performed at Day 2 (24 hours post-dose). 
Phone calls will be conducted 3 days after each on-site visit with the exception of End-of-study 
(EOS) visit. The EOS visit will be completed on site on Day 29. The total duration of the study 
is approximately 8 weeks (56 days), including screening.  
Extended safety monitoring in case of AEs on Day 1 (4 hours after dosing) 
If extended monitoring is required beyond the minimum 4 hours of monitoring on Day 1, the 
following will be assessed: 
• Monitoring of CNS adverse events (dissociation, amnesia, sedation):  
• If there are any dissociative AEs, amnesia or somnolence/sedation present, the 
participant should be monitored at the clinical site until these AEs are fully resolved. 
If the dissociative AEs or cognitive symptoms do not resolve within 6 hours after 
onset, the participant will be required to stay at the clinical site for overnight 
monitoring and can be discharged after the assessments are completed on Day 2 and 
the AEs have resolved. The onset and resolution time of dissociative and cognitive 
AEs should be captured as accurately as possible. The following assessments are 
recommended to follow CNS AEs, whenever possible (e.g., participant is awake):  


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• If dissociative AEs are present, it is recommended to administer the CADSS 
every hour until the total score returns to baseline or normal level (i.e., total score 
not higher than 4) 
• If memory gaps/amnesia is present, it should be assessed with orientation 
questions at least once per hour until the amnesia is resolved  
• Sedation/somnolence should be assessed by questioning or the administration of 
the MOAA/S every hour until the AE is resolved 
• Monitoring of suicidal ideation or behavior:  
• If moderate to severe suicidal ideation or any suicidal behavior is present, either based 
on rating scales or investigator judgment, the investigator must hospitalize the 
participant at least overnight 
• If suicidal ideation is mild, either based on rating scales or investigator judgment, the 
investigator's judgment can be used to allow the participant to leave the clinical 
setting, but in that case arrangements should be made such that family members or 
friends are present with the participant for at least 24 hours. If such arrangements 
cannot be made, it is recommended that the participant is hospitalized at least 
overnight 
• Monitoring of QTcF prolongation:  
• If the initial QTcF prolongation is confirmed by repeated ECG at least 10 minutes 
later, close observation of the participant should be initiated at the investigator’s 
discretion 
• ECG should be performed every 30 minutes until QTcF is below 500 msec and the 
increase from baseline is less than 60 msec 
• Serum electrolyte levels should be determined and corrected, if needed (in particular 
hypokalemia, hypomagnesemia) 
• Consultation with a cardiologist can be performed at the investigator's discretion 
• Monitoring of increased blood pressure:  
• Increase in blood pressure should be monitored but initial treatment is not 
recommended unless clinically indicated. Blood pressure increase associated with 
MIJ821 treatment is usually transient and the blood pressure typically returns to pre-
dose values within 3-4 hours 
• At 1.5 hours post-dose, if SBP is ≥160 mmHg and/or the DBP ≥100 mmHg, 
assessments should continue every 30 minutes until:  
1. The blood pressure is <160 mmHg SBP and <100 mmHG DBP, or 
2. As per investigator’s clinical judgment, the participant is clinically stable, or 
3. The participant is referred for appropriate medical care, if clinically indicated 
4. If the blood pressure remains ≥ 160 mmHg SBP and/or / ≥100 mmHg DBP after 
4 hours post-dose, the participant should be referred for immediate medical 
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The highest dose of s.c. MIJ821 was selected to match the plasma exposure (i.e. Cmax) and RO 
(i.e. maximum RO) to those after i.v. administration of 0.16 mg/kg MIJ821. The latter dose was 
efficacious in the PoC study with i.v. MIJ821 (CMIJ821X2201) and is the highest dose in the 
ongoing Phase 2b dose range study in MDD patients with i.v. MIJ821 (CMIJ821A12201). For 
10 mg s.c. MIJ821, a mean Cmax of 73 ng/mL (range: 36 – 105 ng/mL) was simulated, which 
is only 18% lower than the simulated mean Cmax after i.v. administration of 0.16 mg/kg 
MIJ821 (89 ng/mL, range: 64 – 125 ng/mL). Similar mean maximum RO values were simulated 
for both routes of administration at s.c. 10 mg (95%) and at 0.16 mg/kg (96%). 
In the ongoing SAD study with s.c. MIJ821 (CMIJ821A02101), preliminary results identified 
dissociation as the most common AE (see Section 1.1.3 for details). The incidence of 
dissociation in the SAD study was higher with increasing doses of s.c. MIJ821. At the highest 
dose tested in the SAD study (12 mg MIJ821 s.c.), mild to moderate dissociation occurred in 
approximately 66% of the participants. The safety, tolerability and PK of s.c. MIJ821 might be 
slightly different in TRD patients than in HVs. Therefore, the highest dose of s.c. MIJ821 
selected for the current study is 10 mg, which is slightly lower than the highest dose of s.c. 
MIJ821 (12 mg) tested in the SAD study (MIJ821A02101). 
In summary, 10 mg MIJ821 administered via s.c. route is expected to achieve comparable RO 
profile to 0.16 mg/kg MIJ821 administered i.v., which is known to be efficacious in TRD. The 
10 mg dose of s.c. MIJ821 is also expected to provide an acceptable safety and tolerability 
profile in TRD patients. 
Selection of mid and low dose 
The mid and low doses of s.c. MIJ821 in the current study were selected to minimize the overlap 
between MIJ821 exposure obtained in the different treatment groups and to cover a broad 
exposure range. The mean simulated Cmax (18 ng/mL) of s.c. MIJ821 at the mid dose of 4 mg 
dose is approximately 4.1-fold lower than the mean simulated Cmax at the highest dose of 10 
mg (73 ng/mL). The mean simulated Cmax of s.c. MIJ821 (4 ng/mL) at the low dose of 1 mg 
dose is approximately 4.5-fold lower than the mean simulated Cmax at the mid dose of 4 mg 
(18 ng/mL). The estimated mean maximum ROs of s.c. MIJ821 are 95%, 84% and 54% at the 
10 mg, 4 mg and 1 mg doses, respectively. These doses are therefore expected to reach a broad 
range of maximum RO values. Furthermore, there is a 10-fold difference between the lowest (1 
mg) and highest (10 mg) dose of s.c. MIJ821 used in the current study, which is recommended 
by European Medicines Agency for dose range finding studies EMA 2015. 
In summary, the selected doses of s.c. MIJ821 (1 mg, 4 mg, and 10 mg), cover a 10-fold dose 
range, yield a broad simulated exposure range with minimal risk of exposure overlap between 
dose levels and are also expected to provide a broad range of maximum RO values. 
4.2.2 
Rationale of treatment duration 
The main purpose of the study is to assess the efficacy of MIJ821 to rapidly reduce depressive 
symptoms. As explained in Section 1, a rapid response is meaningful in TRD, a population that 
failed to respond to conventional antidepressants used for adequate duration of time and at 
adequate dose. Depression often leads to suicidal thoughts or behavior, putting patients at risk. 
However, conventional antidepressant treatment might take a few weeks to achieve treatment 




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4.5 
Risks and benefits 
The available safety information, combined with the potential of MIJ821 to effectively treat 
depressive symptoms in patients, suggests a favorable risk-benefit ratio. 
Risks associated with MIJ821 
The risks associated with MIJ821 are summarized in Table 4-1, together with relevant 
preclinical and clinical findings, monitoring and mitigation of risks in the current study. The 
compound related risks were identified in preclinical and clinical studies with MIJ821 and from 
the literature with drugs with similar mechanism of action. 
MIJ821 is an investigational drug that has been tested in a limited number of healthy volunteers 
(HVs) and patients with treatment resistant depression (see Section 1 and the Investigator 
Brochure for details). Risks for MIJ821 as a single agent were identified based on the available 
pre‑clinical and clinical data from MIJ821 as well as data from drugs with similar mechanism 
of action (MoA), i.e. non‑competitive NMDA receptor antagonists. There may be risks 
associated with MIJ821 that have not been identified yet. 
In addition to the above-mentioned important risks, taking into account the class-effects with 
ketamine, and those anticipated due to subcutaneous infection, other potential risks associated 
with MIJ821 include the following events: 
Table 4-1 
Risks associated with MIJ821 
Target organ/Risk;  
Relevant non-clinical and clinical findings with MIJ821 
Monitoring and mitigation in the 
current study 
CNS / Dissociative reactions, Amnesia 
● CNS effects in rats:  
 
● Lack of pinna response at 3 mg/kg in modified Irwin test 
 
● 30 mg/kg/day in preliminary 2‑week study: clinical signs, such as 
ataxia, abnormal gait, impaired righting reflex, decreased motor activity, 
muscle twitches, labored respiration, and/or rales and mortality 
 
● At lower doses: no findings 
● CNS effects in dogs:  
 
● At all doses (1 to 10 mg/kg): transient clinical signs with dose-
dependent severity (abnormal gait, decreased activity, impaired 
coordination, partially closed eyes and salivation) 
 
● In the preliminary study: clonic-tonic convulsions in one dog on a 
non-dosing day following treatment at 3 mg/kg. No such finding in the 
pivotal study at same dose levels 
 
● CNS-related clinical signs in rats and dogs are considered to be 
exaggerated pharmacological effects of MIJ821. 
● FIH study relevant results  
 
● Dissociative AEs were among the most common AEs in the study. 
They were dose dependent, but not observed at 0.16 mg/kg i.v. dose or 
lower. The range for time to onset from start of infusion was 0.78-3.43 
hours and the time to resolution from onset was 1.15-5.35 hours after a 
single dose of MIJ821. 
 
● Amnesia was also among the most common AEs in the study. It 
was observed at 0.32 and 0.48 mg/kg i.v. dose. The range for time to 
onset was 0.83-7.83 hours after start of infusion and the time to 
resolution from onset 0.02-23.85 hours after a single dose of MIJ821. 
● Monitoring at the clinical site for 
minimum 4 hours on the day of 
MIJ821 administration and longer, if 
any dissociative or amnestic AEs 
are observed 
● Routine AE collection and routine 
memory assessment questions 
● Routine AE collection and regular 
administration of the CADSS 
● Participants with current diagnosis 
and history of neurological or 
psychiatric disorders (including drug 
and alcohol abuse) other then TRD 
will be excluded 


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● J-ESS study relevant results  
 
● No dissociative AEs or amnesia were reported in the study at any 
dose of i.v. MIJ821 (0.016-0.16 mg/kg). 
● SAD study with s.c. MIJ821 (study ongoing, preliminary results from 
the first cohorts see Section 1.1.3 for details)  
 
● Preliminary, blinded data with s.c. MIJ821 are available from the 
ongoing double blind, placebo controlled SAD study (MIJ821A02201). 
In this study, Dissociative AEs were reported in the 4 and 12 mg 
cohorts, where MIJ821 exposure was comparable to that reached by 
0.048 and 0.16 mg/kg i.v. doses in the FIH study, respectively. All of 
these events were mild or moderate in severity and resolved without 
treatment. 
● PoC study relevant results  
 
● Dissociative AEs were among the most common AEs in the study 
and were observed at both doses used in the study (0.16 and 0.32 
mg/kg, i.v.). The time to onset was quick (up to 0.7 hour after start of 
infusion), and the time to resolution ranged from 1.6 to 7.0 hours after 
onset. 
 
● Amnesia was also among the most common AEs in the study, it 
was also observed at both 0.16 and 0.32 mg/kg i.v. doses with higher 
incidence at the higher dose. The time to onset was also quick (up to 
0.7 hour after start of infusion), and the time to resolution ranged from 
0.7 to 9.2 hours after onset. 
CNS / Suicidality 
● FIH and J-ESS study relevant results  
 
● No relevant findings were identified based on AEs and the C-
SSRS scale. 
● PoC study relevant results  
 
● Most subjects did not have suicidal behavior or suicidal ideation, 
indicated by the median score for both Sheehan-Suicidality Tracking 
Scale (S-STS) suicidal behavior subscale and S-STS suicidal ideation 
subscale, which were 0 in each treatment group at 24 hours, 48 hours 
and Week 6. 
 
● There were 3 SAEs reported in 2 patients. One patient in the 
MIJ821 0.32 mg/kg biweekly treatment group had suicidal threat during 
the double-blind treatment period and suicide attempt during the follow-
up period (approximately 6 weeks later). One subject in the placebo 
group reported suicide attempt. None of these events were considered 
study drug related. In another patient in the placebo group presented 
suicidal ideation, which was not an SAE, but was considered study drug 
related and lead to discontinuation of treatment. 
● Monitoring at the clinical site for 
minimum 4 hours on the day of 
MIJ821 administration and longer, if 
the participant has severe suicidal 
ideation  
● Routine AE collection 
● C-SSRS scale will be 
administered repeatedly at every 
visit at the clinical site 
● Participant with recent severe 
suicidal ideation or behavior are 
excluded from the study 
Cardiovascular system / QT prolongation 
● Non-clinical tox findings:  
 
● hERG channel IC50 of 1.1 μM 
 
● Late hNav1.5 current IC50 of 6.05 μM 
 
● In dogs: transient increases in heart rate and related shortening of 
the PR and QT intervals, considered non-adverse (transient and of 
modest magnitude) 
● FIH study relevant results  
 
● There were no arrhythmic events of clinical significance, and no 
clinically relevant abnormalities were identified on the numerical ECG 
variables in the Holter and standard safety ECG. 
● Concentration-response (CR) analysis revealed a positive correlation 
between the MIJ821 plasma concentration and the placebo-adjusted 
mean change from baseline in QTcF (ΔΔQTcF). The mean ΔΔQTcF 
● Frequent ECG monitoring, 
particularly during the first 4 hours 
after study drug administration 
● Routine AE collection  
● Patients with history of cardiac 
disorders or QTcF ≥450 msec 
(male) or ≥460 msec (female) are 
excluded from the study 


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exceeded the threshold of 5 ms at the Cmax of 0.16 mg/kg (6.3 ms). 
The upper bound of the two-sided 90% CI remained below 10 ms at 
exposures below the Cmax of 0.16 mg/kg. 
● J-ESS study relevant results  
 
● CR analyses revealed a positive correlation between the MIJ821 
plasma concentration and ΔΔQTcF. The mean ΔΔQTcF was 5.584 ms 
and the upper bound of the two-sided 90% CI was 11.732 ms at the 
geometric mean Cmax of 0.16 mg/kg dose. 
● PoC study relevant results  
 
● One subject (0.32 mg/kg MIJ821 biweekly) had new-onset atrial 
fibrillation recorded as an SAE, which was not considered study drug 
related. 
Cardiovascular system / Increased blood pressure 
● FIH study relevant results  
 
● CR analyses also revealed positive correlations between the 
MIJ821 plasma concentration and the placebo-adjusted mean change 
from baseline in systolic and diastolic blood pressure (ΔΔSBP and 
ΔΔDBP). 
 
● The mean ΔΔSBP and mean ΔΔDBP at the Cmax of 0.16 mg/kg 
was 18.6 and 10.7 mmHg, respectively. 
● J-ESS study relevant results  
 
● CR analysis revealed a positive correlation between MIJ821 
plasma concentration and placebo-adjusted change from mean 
baseline in the systolic and diastolic BP (SBP and DBP). 
 
● At the geometric mean Cmax MIJ821 0.16 mg/kg, the mean 
ΔΔSBP and ΔΔDBP were 23.852 and 16.413 mmHg, respectively. 
● PoC study relevant results  
 
● Increased blood pressure was reported as AE in 3 subjects 
receiving MIJ821 (2 subjects in the MIJ821 0.16 mg/kg weekly 
treatment group, and 1 subject in the MIJ821 0.16 mg/kg every other 
week treatment group). All these elevations were detected within 2 
hours after administration of study treatment. All these AEs were of mild 
or moderate severity and resolved on the same day or next day without 
intervention except one of the AEs in one subject (MIJ821 0.16 mg/kg 
every other week) which lasted more than 1 week (from Day 29 to Day 
37). 
● Frequent monitoring of vitals, 
particularly during the first 4 hours 
after study drug administration 
● Routine AE collection  
● Patients with Grade 2 or higher 
grade hypertension are excluded 
from the study 
 
• Sedation 
Sedation is a known class effect for NMDA inhibitors. Administration of MIJ821 was 
associated with development of sedation in early clinical studies. In early studies, sedation 
showed dose dependence, the time to onset for sedation was short, and most events occurred 
within 40 minutes of infusion. 
Sedation in the current study will be monitored by AE collection and by the MOAA/S scale. 
Given that MIJ821 may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, participants should be 
advised about these potential risks. If the participant is feeling drunk or dizzy or if he/she 
experiences visual disturbances, hallucinations, or euphoric mood, then he/she should not drive, 
use machines or perform any other tasks that require his/her attention and good coordination. 
In case of a safety concern, the participant should be hospitalized (or hospitalization should be 


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prolonged) as per investigator's judgement until resolution of these events or absence of a safety 
risk. 
• Respiratory effects 
MIJ821 demonstrated an increase in respiration rate of 23% at 3 mg/kg in the rat 
FOB/respiratory safety pharmacology study. However, ketamine might have a negative impact 
on respiratory function when administered rapidly, particularly at high doses. Ketamine at 
anesthetic dosages is considered relatively safe because protective airway reflexes are 
preserved. There are no reports of respiratory distress with ketamine i.v. at dosages of 0.3-0.5 
mg/kg with 40 minute infusions that have been administered in depression participants. In the 
PoC study, no specific respiratory effect related signal was noted. 
Respiratory effects will continued to be assessed in the study using adverse event data. 
• Cystitis or other lower urinary tract adverse events. 
Cases of ulcerative or interstitial cystitis have been reported in individuals with long-term off-
label use or misuse/abuse of ketamine. In clinical studies with Spravato (esketamine) nasal 
spray, there was a higher rate of lower urinary tract symptoms (pollakiuria, dysuria, micturition 
urgency, nocturia, and cystitis) in Spravato treated participants than in placebo-treated 
participants. No cases of esketamine-related interstitial cystitis were observed in any of the 
studies, which included treatment for up to a year. 
Cystitis and other urinary symptoms will be monitored in the current study by AE collection 
and urinalysis. 
• Injection site reactions and hypersensitivity 
The risks associated with s.c. administration includes injection site reactions and 
hypersensitivity. Results of the SAD study in HVs with s.c. MIJ821 indicate that local 
tolerability of MIJ821 administered via the s.c. route was good. Mild pain, pruritus and bruising 
occurred in each dose group. All events were mild and self limiting. 
In general, hypersensitivity can manifest with itching, flushing, headache, nausea/vomiting, 
hypotension, urticaria, bronchospasm, or angioedema. In the event of a hypersensitivity 
reaction, assess and treat for anaphylaxis, if indicated, and initiate supportive care as per local 
practice. Fluids, vasopressors, corticosteroids, antihistamines, bronchodilators, and oxygen 
should be at hand. 
Potential MIJ821-related risks to the fetus and prevention of pregnancies: 
MIJ821 is not genotoxic. Pivotal EFD studies in rats and rabbits showed that MIJ821 is not 
teratogenic. While MIJ821 was well tolerated in rats in the absence of maternal or embryofetal 
toxicity, treatment of pregnant rabbits with MIJ821 was associated with embryo lethality at 
maternally toxic dose levels. The NOAEL for maternal and fetal effects was established at 3 
mg/kg/day which is associated with an AUC-based safety margin of 5.9-fold when compared 
with 0.16 mg/kg human dose. 
Taking the study treatment may involve unknown risks to the fetus if pregnancy were to occur 
during the study. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 


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study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they should not be entered or continue in the study. 
COVID-19 related risks 
If the Coronavirus Disease (COVID-19) pandemic limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by Novartis. Phone calls, 
virtual contacts (e.g., teleconsult) or visits by site staff/home nursing service to the participant´s 
home depending on local regulations and capabilities, can replace on-site study visits, for the 
duration of the pandemic until it is safe for the participant to visit the site again. The collection 
of samples may also be modified by the Sponsor and will be communicated to the Investigator. 
Please refer to the Investigator's brochure on additional details on the risks and mitigation 
measures. 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 8 
weeks, from each participant as part of the study. The approximate volumes are mentioned in 
the informed consent form (ICF). Additional samples may be required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment information are also available in the laboratory manual. 
See the Section 8.5.3.1. on the potential use of residual samples. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
Approximately 56 participants with TRD will be randomized to receive either MIJ821 1 mg, 
MIJ821 4 mg, or MIJ821 10mg or placebo, in addition to standard pharmacological 
antidepressant SoC treatment, in a 1:1:1:1 ratio in a total of 20-25 centers worldwide. 
TRD is defined based on retrospective assessment of antidepressant treatment failure as per 
treatment history, as specified in the Inclusion criteria below. 
The investigator must ensure that all participants being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order that the study population will be representative of all eligible participants. 


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Participants selection is to be established by checking through all eligibility criteria at screening 
and the relevant eligibility criteria at baseline. A relevant record (e.g., checklist) of the eligibility 
criteria must be stored with the source documentation at the study site. 
Deviation from any entry criterion excludes a participant from enrollment into the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male and female participants, 18 to 65 years of age (inclusive) at screening. 
3. Participant has a diagnosis of recurrent MDD and a current major depressive episode of at 
least 8 weeks in duration as defined by DSM-5 criteria and confirmed by both the SCID-5 
and an adequate clinical psychiatric evaluation at screening. 
4. MADRS ≥ 24 at screening and before randomization on Day 1. 
5. Failure to respond to 2 or more antidepressant treatments but no more than 5, where the 
two failed treatments are two different antidepressants and at least one of which was used 
in the current depressive episode, with adequate dose and duration (≥ 6 weeks duration, 
doses defined per agent), as identified by the MGH-Antidepressant Treatment Response 
Questionnaire, based on the patient's report and prior psychiatric history, assessed by the 
investigator, and further documented by medical records. Patients with historical treatment 
failure to esketamine, ketamine or arketamine are excluded. 
6. Participant must agree to receive pharmacological standard of care treatment to treat their 
MDD (as determined by the treating physician(s) based on clinical judgement and 
protocol recommendations) during the trial duration. 
7. If the participant is taking any other type of psychotropic drugs, the dose of these drugs 
needs to be stable, where a stable dose of psychotropic drugs is defined as no changes in 
dose or type of e.g. antipsychotics or mood stabilizers for at least 6 weeks prior to baseline 
(if applicable). 
8. The antidepressant should be at a stable dose for at least 4 weeks before baseline. No new 
antidepressant initiated 6 weeks or less before baseline. No psychotherapy initiated 4 
weeks or less before baseline. 
9. Able to communicate well, and to understand and comply with study requirements. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study: 
1. Current acute depressive episode lasting longer than two years continuously, or 
participants receiving electroconvulsive therapy (ECT), transcranial magnetic stimulation 
(TMS), vagus nerve stimulation (VNS) or deep brain stimulation (DBS) in the current 
episode or within last year prior to screening (whichever is longer). 
2. Any prior or current diagnosis of MDD with psychotic features, bipolar disorder, 
schizophrenia, or schizoaffective disorder as obtained from SCID-5 at screening. 
3. Participants with acute alcohol or substance use disorder or withdrawal symptoms 
requiring detoxification, or participants who went through detoxification treatment 


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(inpatient or outpatient) within 1 month before Screening, as obtained from SCID-5 at 
screening. 
4. Participants with current borderline personality disorder or antisocial personality disorder 
assessed at Screening, based on DSM-5 criteria and investigator judgment. 
5. Current clinical diagnosis of autism, dementia, or intellectual disability. 
6. Participants with a history of suicidal attempt or suicidal behaviour within last year prior 
to screening and participants presenting suicidal ideation with intent documented by C-
SSRS by Yes response to Q4 or Q5 at screening or baseline. 
7. Participants with evidence of significant renal insufficiency, indicated by an estimated 
glomerular filtration rate (eGFR) of <40 mL/min/1.73 m2 at screening. 
8. Use of other investigational drugs at the time of screening, or within 30 days or 5 
half‑lives of screening, whichever is longer. 
9. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar mechanism of action (i.e. drugs that affect the NMDA receptor).  
10. Active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus 
(HIV) or active COVID-19 infection as per medical history and/or available medical 
records. 
11. History of seizures. Note: childhood febrile seizures are not exclusionary. 
12. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction, angina pectoris, or coronary artery bypass graft 
within 6 months prior to starting study treatment 
• History of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., 
bifascicular block, Mobitz type II and third degree AV block) within 6 months prior 
to starting study treatment 
13. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or baseline. 
14. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia or any of the following: 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome 
• Concomitant medication(s) with a “Known Risk of TdP” that cannot be discontinued 
or replaced by safe alternative medication 
15. Participant has mean systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 
mmHg at Screening or pre first dose on Day 1; or past history of hypertensive crisis. 
16. History of hemorrhagic stroke or known cerebrovascular disorders (e.g. aneurysm or 
arteriovenous malformation) or known aneurysmal vascular disease in other location (e.g. 
aorta). 
17. Pregnancy (including a positive human chorionic gonadotropin [hCG] test) or lactation at 
screening or baseline. 
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 


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during dosing and for 1 week after stopping of investigational drug. Highly effective 
contraception methods include: 
• Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that participant. 
• Use of intrauterine device (IUD) or intrauterine system (IUS). In case of use of an 
IUD or IUS, the device or system should have been placed and well tolerated by the 
patient for a minimum of 3 months before taking the study treatment. 
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception other forms of hormonal contraception are not allowed for the purpose of 
contraception.   
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the ICF. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. Refer to Section 8.4.3 (Pregnancy and Assessments of 
Fertility).  
19. Sexually active males unwilling to use a condom during intercourse while taking 
investigational drug and for 1 week after stopping study treatment. A condom is required 
for all sexually active male participants to prevent them from fathering a child AND to 
prevent delivery of the investigational drug via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the time period specified above.   
20. Participants taking medications prohibited by the protocol (see Section 6.2.2) 
21. Any other condition (e.g. known liver disease/liver dysfunction, active malignancy etc.) 
which in the opinion of the investigator would put the safety of the participant at risk, 
affect compliance or make the patient an unsuitable candidate for the study. 
General Note: In the case where a safety laboratory assessment at screening and/or 
baseline is outside of the range specified above, the assessment may be repeated once 
prior to randomization. If the repeat value remains outside of the specified ranges, the 
participant is excluded from the study. 


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6 
Treatment 
6.1 
Study treatment 
Study treatment consists of MIJ821 or placebo. MIJ821 20 mg will be supplied centrally as 
lyophilized powder in vials (pharmaceutical form). 
MIJ821 20 mg will be reconstituted with water for injection to obtain the solution for injection 
for all MIJ821 doses. Placebo will consist of 0.9% sodium chloride infusion bags supplied by 
the site. 
The s.c. injection of study treatment (Day 1) must be administered while the participant is at 
site. 
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for participant numbering, prescribing/dispensing, and administration of study 
treatment are outlined in the Pharmacy Manual. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control 
Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
MIJ821 20 mg 
Lyophilisate in vial 
Powder for solution 
for injection 
Injection use (after 
reconstitution) 
Open label supply, 
vials (one vial per kit) 
Sponsor (global) 
Placebo 
0.9% sodium 
chloride solution 
Injection use 
Open label; infusion 
bag/bottle 
Locally by site 
The investigational treatment for this study is MIJ821. Due to the difference in preparation 
between MIJ821 and placebo, unblinded qualified site personnel, independent from the 
investigational staff, are required to maintain the blind. Please refer to Section 6.5 for additional 
details. 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug, control drug (placebo), and pharmacological 
antidepressant SoC are included in this trial. 
Pharmacological antidepressant SoC treatment in the study will consist in antidepressants or 
combinations of antidepressant with other drugs used for depression augmentation. It is 
recommended that antidepressants used as background therapy during the study are FDA 
approved for MDD indication (see protocol Appendix 6 Section 16.6: Antidepressants 
recommended to be used as background therapy during the study). 
6.1.3 
Treatment arms/group 
Participants will be randomly allocated to one of the following four treatment arms in a 1:1:1:1 
ratio, on Day 1: 
• Single administration of MIJ821 10 mg, one s.c. injection 
• Single administration of MIJ821 4 mg, one s.c. injection  


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• Single administration of MIJ821 1 mg, one s.c. injection 
• Single administration of placebo, one s.c. injection 
6.1.4 
Treatment duration 
Participants will receive a single s.c. injection on Day 1.  
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions, SARS-CoV-2 vaccine) administered after the participant was enrolled into 
the study must be recorded in the concomitant medications/significant non-drug therapies CRF. 
The investigator should instruct the participant to notify the study site about any new 
medications he/she takes after the participant is enrolled in the study. All medications, 
procedures and significant non-drug therapies administered after the participant is enrolled into 
the study must be recorded. The start and stop date and time of each medication use should be 
recorded as precisely as possible. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. 
All allowed concomitant baseline psychotropic medications used for treatment of depression 
must be documented as Standard of Care (SoC) and remain unchanged throughout the study. 
Any change in SoC after randomization (dose changing or starting new drugs) should be 
documented in medical records and reported in the eCRF. 
Certain benzodiazepines, specifically lorazepam or alprazolam (as authorized by country), will 
be allowed for episodic or chronic use. These should not be taken within 12 hours before 
and within 4 hours after dosing unless it is used as rescue medication not to exceed 2 mg 
in a 24-hour period. Such lorazepam or alprazolam use will be documented as concomitant 
medication(s) and administration time should be documented in medical records and reported 
in the eCRF. 
Any vaccinations should not be administered within 2 days prior to randomization. 
For participants taking strong CYP2D6 inhibitors (e.g., berberine, bupropion, dacomitinib, 
fluoxetine, paroxetine, quinidine), the immediate time period after s.c. administration should be 
monitored with extra caution. All safety observations should be carefully observed for increased 
or unexpected frequency and severity. 
Based on nonclinical information, MIJ821 is predicted to be eliminated predominately by 
oxidative metabolism via CYP2D6 (64% of elimination). Inhibition of the elimination pathways 
may lead to an increase of MIJ821 exposure. The following investigations have been executed 
to assess the potential drug-drug interaction on the major elimination pathway via CYP2D6: 
• The impact of strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine and bupropion) on 
the exposure of i.v. infused MIJ821 has been investigated in drug-drug interaction (DDI) 
simulations by means of the SimCYP® software. The simulated Cmax values were in 


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maximum 1.3-fold higher in the presence of fluoxetine or paroxetine and the AUC values 
in maximum 2-fold for all CYP2D6 genotypes (poor, extensive, or ultra-metabolizers). 
The resulting mean exposure values in the presence of strong CYP2D6 inhibitors are 
within the exposure range investigated in the FIH study after i.v. infusion 
(CMIJ821X2101, doses: 0.016, 0.048, 0.16, 0.24, 0.32 and 0.48 mg/kg). For the strong 
CYP2D6 inhibitor bupropion, no drug-drug interaction was estimated. Comparable impact 
of the MIJ821 exposure is expected after s.c. administration in the presence of strong 
CYP2D6 inhibitors since the i.v. and s.c. routes of administration are comparable in terms 
of circumventing the liver first-pass. Following s.c. administration of the highest dose (12 
mg) in the s.c. SAD study with HVs (CMIJ821A02101), the exploratory mean AUClast 
and Cmax values are 257 h*ng/mL and 77.4 ng/mL, respectively, being comparable to the 
exposure values after i.v. infusion of 0.16 mg/kg MIJ821 in the FIH study 
(CMIJ821X2101). As discussed above, the mean exposure values after s.c. administration 
of the highest dose in this study (10 mg) are within the exposure range investigated in the 
FIH study in the presence of strong CYP2D6 inhibitors. 
• Furthermore, in the PoC study (CMIJ821X2201, doses: 0.16 and 0.32 mg/kg), 
approximately 70% of participants received at least one CYP2D6 inhibitor (weak to strong 
CYP2D6 inhibitor or combinations of them). The Cmax values at both doses and the AUC 
values at 0.16 mg/kg do not exceed the exposure range determined in the FiH study. 
Based on overall clinical experience (CMIJ821X2101, CMIJ821X2201), the totality of the 
safety data suggest that MIJ821 is generally safe and well tolerated and observed adverse events 
were transient. The risk of an overdose or unexpected AEs due to an exposure increase by 
CYP2D6 inhibition is considered to be low for the proposed MIJ821 doses being less or equal 
to 10 mg. In conclusion, CYP2D6 inhibitors are allowed as co-medications. Nevertheless, 
caution has to be taken when strong CYP2D6 inhibitors are administered. 
Based on nonclinical information, MIJ821 may affect the elimination of compounds eliminated 
predominantly via CYP3A4 and CYP2D6. The impact of MIJ821 on the exposure of 
midazolam (CYP3A4 substrate) and desipramine (CYP2D6 substrate) has been investigated in 
drug-drug interaction (DDI) simulations by means of SimCYP® software. No exposure increase 
of both probe substrates has been estimated at the highest tested MIJ821 dose of 0.48 mg/kg 
after i.v. infusion. Therefore, the risk of an overdose or unexpected adverse events of co-
administered sensitive CYP3A4 and CYP2D6 substrates is considered to be not significant at 
s.c. doses of ≤ 10 mg MIJ821. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Refer to Section 6.2.1. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed at the time points listed. This 
list of medications is not exhaustive. Each medication should be evaluated for its potential 
additive effect(s) of sedation, dissociation, suicidality, cardiovascular and respiratory effects, 
as well as impact on memory and cognitive functions. Medications with a potential impact 
should be avoided for at least one half-life of the medication before each study visit and one 
half-life after each study drug administration. 


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Table 6-2 
Prohibited Medications or Treatment 
Medication 
Prohibition period 
Action taken to study 
treatment**  
Reason 
Ketamine, Esketamine, 
Arketamine 
2 months before 
Screening and during the 
whole study duration 
Do not administer study 
treatment 
Safety and PD interaction 
-additive effects (NMDA 
receptor antagonists) 
ECT, transcranial 
magnetic stimulation 
(TMS), Deep brain 
stimulation (DBS), and 
Vagus nerve stimulation 
(VNS) 
From screening and 
during the whole trial 
duration 
Do not administer study 
treatment 
PD interaction 
Amantadine 
From screening and 
during the whole trial 
duration 
Do not administer study 
treatment 
Safety (CNS additive 
effects) and PD 
interaction (weak non-
competitive NMDA 
receptor antagonist) 
Monoamine oxidase 
inhibitors (MAOIs) 
From screening 
(minimum 14 days before 
baseline) and during the 
whole trial duration 
Do not administer study 
treatment 
Safety (additive risk of 
hypertension effect and 
potential for precipitating 
hypertensive crisis) and 
PD interaction 
Citalopram, Escitalopram 
From Screening and 
during the whole trial 
duration 
Do not administer study 
treatment 
Safety (additive risk of 
QT prolongation, known 
risk of Torsades de 
Pointes) 
Medications with a 
Known Risk of Torsades 
de Pointes according to 
Section 16.5 and 
https://crediblemeds.org/ 
7 days before and 7 days 
after the study drug 
injection. 
Do not administer study 
treatment 
Safety (additive risk of 
QT prolongation, risk of 
Torsades de Pointes) 
Amitryptyline, 
Nortryptyline 
Within 24 hours prior to 
study drug injection and 
up to at least 4 hours 
after study drug injection 
Do not administer study 
treatment 
Safety (additive risk of 
QT prolongation, risk of 
Torsades de Pointes) 
Quetiapine 
Within 12 hours prior to 
study drug injection and 
up to at least 4 hours 
after study drug injection 
Do not administer study 
treatment 
Safety (additive risk of 
QT prolongation, risk of 
Torsades de Pointes) 
Oral and Systemic 
Hormonal Contraceptives 
for contraception 
purposes 
From Baseline and up to 
1 week after study drug 
injection 
Do not administer study 
treatment 
Not accepted as highly 
effective contraception 
until a dedicated clinical 
study shows no drug-sruf 
interaction between 
MIJ821 and hormonal 
contraceptives. 
Systemic Corticosteroids 
Chronic use is prohibited 
from Screening and until 
the end of study 
Do not administer study 
treatment 
Safety (additive 
cardiovascular and 
neuropsychiatric effects) 
Cough decongestants 
Within 12 hours prior to 
study drug injection and 
up to at least 4 hours 
after end of study drug 
injection 
Do not administer study 
treatment 
Safety (additive sedative 
effects) and confounding 
effect for safety 
assessments 
Benztropine and 
diphenhydramine 
Within 12 hours prior to 
study drug injection. 
Do not administer study 
treatment 
Safety (additive sedative 
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Medication 
Prohibition period 
Action taken to study 
treatment**  
Reason 
Continuous use is 
prohibited. 
effect for safety 
assessments 
Benzodiazepines 
Within 12 hours prior to 
and 4 hours after study 
drug injection 
Do not administer study 
treatment 
Safety (adding sedative 
effect and confounding 
effect for safety 
assessments) 
Trazodone 
Within 24 hours prior to 
and 24 hours after study 
drug injection 
Do not administer study 
treatment 
Safety (additive Risk of 
QT prolongation) 
Alcohol 
Within 24 hours prior to 
and 24 hours after study 
drug injection* 
Do not administer study 
treatment 
Safety (additive sedative 
and CNS effects), 
confounding effect for 
safety and efficacy 
assessments 
Cannabis, medical 
marijuana and 
psychostimulants 
(amphetamines, 
methylphenidate, 
modafanil, armodafinil 
etc.) 
Within 24 hours prior to 
each study visit and 24 
hours after study drug 
injection* 
Do not administer study 
treatment 
Safety (additive CNS 
effects), confounding 
effect for safety and 
efficacy assessments 
Opioids 
Within 24 hours prior to 
each study visit and 24 
hours after study drug 
injection* 
Do not administer study 
treatment 
Safety (additive sedative 
and CNS effects), 
confounding effect for 
safety and efficacy 
assessments 
* In case of a prohibited use or when a participant appears intoxicated at the visit (e.g., alcohol, etc.), visit 
reschedule should be considered as per the permitted visit window 
** Participants who are in the post dose follow-up period should continue the follow-up even if they are taking 
prohibited medications. 
6.2.3 
Rescue medication 
Rescue medications will not be supplied by the sponsor. 
The following rescue medications may be considered and the use of these should be documented 
in the medical records and in the eCRF: 
For agitation and anxiety or aggressive behavior (per investigator's judgment or local clinical 
practice): as required, midazolam (maximum dose 2.5 mg orally or intramuscular), any short-
acting benzodiazepine (e.g., lorazepam), or antipsychotics (e.g., quetiapin, olanzapine, 
promethazin, or dipiperon). 
Prohibited medication (see Table 6-2) can be administered as rescue medication at any time if 
clinically warranted. 
6.2.4 
Restriction for study participants 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 


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6.2.4.1 
Dietary restrictions and smoking 
No dietary or smoking restrictions in this study. 
Participants should not consume alcohol or cannabis 24 hours before each study visit. If the 
participant appears intoxicated at the visit (e.g., alcohol, marijuana, other agent), a visit 
reschedule should be considered.  
6.2.4.2 
Other restrictions 
If the participant is feeling drunk or dizzy of if he/she experiences visual disturbances, 
hallucinations, or euphoric mood, then the participant should not drive, use machines or perform 
any other tasks that require his/her attention and good coordination. 
6.3 
Preparation and dispensation 
Each study site will be supplied with the investigational treatment (MIJ821) in packaging as 
described under investigational and control drugs section (Section 6.1.1). 
For the study treatment (MIJ821 or placebo) preparation prior to administration, please refer to 
the Pharmacy Manual. 
Qualified unblinded site personnel will identify the study treatment to dispense to the participant 
by contacting the Interactive Response Technology (IRT). The investigational treatment 
(MIJ821) is labeled and a unique medication number is printed on the label. Immediately before 
dispensing the investigational treatment kit, the qualified unblinded personnel will report the 
unique medication number in the source document. 
Placebo will be sourced locally. The study site must capture in the drug accountability log the 
name of the placebo manufacturer, the batch number and expiry date. For details on preparation, 
refer to the Pharmacy Manual. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a qualified unblinded site personnel at the study site, 
handled and stored safely, properly, and kept in a secured location to which only the qualified 
unblinded site personnel have access. Upon receipt, all study treatments must be stored 
according to the instructions specified on the labels.  
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Investigational treatment labels will be in the local language and comply with the legal 
requirements of each country. They will include storage conditions for the study treatment but 
no information about the participant except for the medication number. 
The qualified unblinded site personnel must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by unblinded monitors during site or remote monitoring visits, and/or at the 
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At the conclusion of the study, and as appropriate during the course of the study, the qualified 
unblinded site personnel may destroy and document destruction of unused study treatment, drug 
labels and packaging as appropriate in compliance with site processes, monitoring processes, 
and per local regulation/guidelines. Otherwise, the qualified unblinded site personnel will return 
all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis unblinded monitor or to the Novartis address provided in the 
investigator folder at each site. 
6.3.1.2 
Handling of other treatment 
No additional treatment beyond investigational drug and placebo are included in this trial. 
6.3.2 
Instruction for prescribing and taking study treatment 
Study participants will receive one of the following study treatments as a single s.c. injection: 
MIJ821 (10 mg, 4 mg, 1 mg) or placebo. 
The study treatment will be administered as a single s.c. injection in the abdominal area, above 
(i.e., cranial to) the line of the umbilicus, but not within 5 cm from the umbilicus. The injection 
must not be administered in an area with scars, inflammation, proliferative skin disease 
(including nevus), tattoo, burn or other abnormalities of the skin. The injection must be 
administered by trained staff with appropriate technique and by considering the participant’s 
body shape (e.g., thickness of local subcutaneous tissue). For thin participants, using the skin-
fold technique is recommended. The injection will be administered slowly (over 15-30 sec). 
Care must be taken not to administer the study treatment as intramuscular injection, as that 
might change the PK and consequently the safety and efficacy profile of MIJ821. 
Please refer to the Pharmacy Manual for further details. 
Study treatment (MIJ821 or placebo) will be assigned by the IRT and will be recorded in the 
IRT system. 
Each study site will be supplied with investigational treatment (MIJ821) kits as described in 
Section 6.1.1 (Investigational and control drugs). 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 


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A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. Re-
screening for patients will only be allowed once. 
6.4.2 
Treatment assignment, randomization 
On Day 1, all eligible participants will be randomized via Interactive Response Technology 
(IRT) to one of the treatment arms. The qualified site personnel will contact the IRT after 
confirmation from the investigator or his/her delegate that the participant fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the participant, 
which will be used to link the participant to a treatment arm. If the participant is allocated to the 
placebo treatment arm, IRT will not return any kit allocation. If the patient is allocated to the 
active treatment arm, IRT will assign a unique medication number. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
Randomization will be stratified by class of current anti-depressant standard of care (Selective 
Norepinephrine Reuptake Inhibitors (SNRI), Selective Serotonin Reuptake Inhibitors (SSRI) or 
other anti-depressants or combination of anti-depressants). 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
The unblinded qualified site personnel MUST NOT communicate information about 
medication numbers to anyone involved in the study (i.e., site personnel including the 
investigator, participant, sponsor) with the exception of the unblinded monitor and the clinical 
staff managing the drug supply to site. If accidentally communicated, the Novartis unblinded 
monitor should be notified. 
6.5 
Treatment blinding 
Participants, investigator staff, and persons performing the assessments will remain blind to the 
identity of the treatment from the time of randomization until database lock using the following 
methods: (1) Randomization data are kept strictly confidential until the time of unblinding and 
will not be accessible by anyone else involved in the study with the following exceptions: GCS 
and the PK analysts team; (2) the identity of the treatments will be concealed by the involvement 
of unblinded qualified site personnel for study treatments preparation and administration. 
Open label supply of MIJ821 will be provided to the unblinded qualified site personnel who 
must remain independent from other site staff in order to maintain the blind. The study 
treatments will be prepared by an unblinded qualified site personnel, and administration will be 
performed by an unblinded administrator. Both must be independent and not be involved in any 
study assessments. Preparation and administration of study treatments can also be performed 


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by a single unblinded qualified site personnel, if authorized to complete both activities. 
Instructions for prescribing/dispensing and administration are outlined in the Pharmacy Manual. 
To minimize the risk of introducing bias, different site personnel must perform efficacy and 
safety assessments as described in Section 8.3.1 . 
The randomization codes associated with participants from whom PK samples are taken will be 
disclosed to the PK bioanalyst, who will keep PK results confidential. The randomization codes 
may also be disclosed to designated pharmacometric team members. 
At the time of interim analysis planned for internal purpose (i.e., when approximately 50% of 
participants have completed study (or discontinued prior to Day 29), the designated Novartis 
pharmacometric team members will be unblinded. The results of this interim analysis will be 
restricted to the designated pharmacometric members. 
The Data Monitoring Committee (DMC) will conduct ongoing unblinded safety reviews. There 
will be unblinded statisticians and programmers in charge of DMC reporting activities (for more 
details on DMC, see Section 10.3.1). 
Unblinding a participant at site, for safety reasons (necessary for participant management), will 
occur via an emergency system in place at site. 
6.6 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
Injections will be administered at site. This information must be captured in the source 
document, the appropriate CRF(s) and in the Drug Accountability log. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with MIJ821, as detailed in Section 8.5.2. 
6.7.2 
Recommended treatment of adverse events 
AEs must be treated according to local guidelines relevant for the symptoms. 
Medication used to treat AEs must be recorded on the appropriate CRF. 
6.7.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The investigator will then receive details of the 


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investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
A participant cannot continue the study after an emergency break. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant during the study as needed. Any new information 
regarding the safety profile of the investigational drug that is identified between IB updates will 
be communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also includes:  
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• As applicable, the Information Sheet for the Female Partner of Male Study Participants 
which highlights the need for the use of highly effective methods of contraception 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
 
 


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Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
Participants will be asked to complete an optional Trial Feedback Questionnaire (TFQ) to 
provide feedback on their clinical trial experience. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all study assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should attend on-site study visits as outlined in the assessment schedule (Table 8-1) 
or as close to the designated day/time as possible. This is especially important for the Day 2 
visit at which primary efficacy assessments are performed. Missed or rescheduled visits should 
not lead to automatic discontinuation. In addition, the participant will be contacted by phone in 
between on-site visits (Follow-up call) to collect information about adverse events and 
concomitant medications. In case follow-up calls have to be shifted by +/- 3 days, follow-up 
calls can be replaced by on-site visits in accordance to the original visit schedule. 
In case a visit is performed outside the schedule, subsequent visits shall be performed in 
accordance to the original visit schedule. In addition to the scheduled visits, participants may 
have unscheduled visits for safety monitoring purposes at the discretion of the Investigator. 
Data collected during unscheduled visits will be recorded in the unscheduled visit CRFs. 




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Table 8-1 
Assessment Schedule 
Period Screening 
Treatment 
Follow-up 
Visit Name Screening 
Treatment 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
End 
of 
Study 
visit 
Visit Numbers1 
1 
20 
40 
50 
60 
70 
80 
90 
100 
110 
120 
Days -28 to -1 
1 
2 
4 
8 
11 
15 
18 
22 
25 
29 
Time (post-dose) 
- 
-
1h 0h 0.17h 0.33h 0.5h 0.75h 1h 1.5h 2h 4h 24h 
- 
- 
- 
- 
- 
- 
- 
- 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical 
conditions 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
SCID-5 
S3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MGH-ATRQ 
S3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Alcohol Test and 
Drug Screen  
S3 
S3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy and 
assessments of 
fertility4 
X 
X5 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Physical 
Examination 
S3 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S3 


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Period Screening 
Treatment 
Follow-up 
Visit Name Screening 
Treatment 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
End 
of 
Study 
visit 
Visit Numbers1 
1 
20 
40 
50 
60 
70 
80 
90 
100 
110 
120 
Days -28 to -1 
1 
2 
4 
8 
11 
15 
18 
22 
25 
29 
Time (post-dose) 
- 
-
1h 0h 0.17h 0.33h 0.5h 0.75h 1h 1.5h 2h 4h 24h 
- 
- 
- 
- 
- 
- 
- 
- 
Body 
Temperature 
X 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
Blood Pressure 
and Pulse Rate 
X 
X6 
  
  
  
X 
  
  
X 
  X 
X 
  
X 
  
X 
  
X 
  
X 
Respiratory rate3 
S 
S 
  
  
  
S 
  
  
S 
  S 
S 
  
S 
  
S 
  
S 
  
S 
Oxygen 
Saturation 
  
S3,7 
  
  
  
  
  
  
  
  
  
Electrocardiogram 
(ECG) 
X 
X6 
  
  
  
X 
  
  
X 
  X 
X 
  
  
  
  
  
  
  
X 
CADSS 
  
X 
  
  
  
X 
  
  
X 
  X 
X 
  
X 
  
X 
  
X 
  
X 
MOAA/S 
  
X 
  
  
  
X 
  
  
X 
  X 
X 
  
X 
  
X 
  
X 
  
X 
Memory 
Assessment 
Questions13 
  
  
  
  
  
S 
  
  
  
  
S 
S 
  
  
  
  
  
  
  
  
C-SSRS 
X 
X 
  
  
  
  
  
  
  
  X 
X 
  
X 
  
X 
  
X 
  
X 
Local tolerability 
assessment 
  
  
  
  
  
S 
  
  
  
  S 
S 
  
  
  
  
  
  
  
  
Hematology 
X11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
Clinical Chemistry 
X11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
Coagulation 
Panel 
X11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
Urinalysis 
X11 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
X 
PK blood 
collection 12 
  
  X8 
X 
X 
X 
X 
X 
X 
X X 
X9 
  
  
  
  
  
  
  
  


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Period Screening 
Treatment 
Follow-up 
Visit Name Screening 
Treatment 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
Follow-
up 
visit 
Follow-
up call 
End 
of 
Study 
visit 
Visit Numbers1 
1 
20 
40 
50 
60 
70 
80 
90 
100 
110 
120 
Days -28 to -1 
1 
2 
4 
8 
11 
15 
18 
22 
25 
29 
Time (post-dose) 
- 
-
1h 0h 0.17h 0.33h 0.5h 0.75h 1h 1.5h 2h 4h 24h 
- 
- 
- 
- 
- 
- 
- 
- 
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dose 
administration 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
MADRS 
X 
X 
  
  
  
  
  
  
  
  X 
X 
  
X 
  
X 
  
X 
  
X 
Concomitant 
therapies 
X 
X 
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
  
X 
  
X 
  
  
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study completion 
information 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Safety follow-up 
call 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit structure given for internal programming purpose only 
2 Optional for participant 
3 S = assessment to be recorded on source documentation only and will not be entered into the eCRF. If drug screen result is positive but does not meet DSM-5 criteria for substance use 


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disorder, the subject can be randomized. 
4 Additional pregnancy testing may be performed at each visit to meet local requirements. Serum pregnancy test to be performed, unless specified otherwise. 
5 Urine pregnancy test. Dosing can proceed only if result is negative.  
6 Dosing can proceed if the results are deemed satisfactory by the Investigator. 
7 Every 15 minutes from pre-dose to 4 hours post-dose 
8 Pre-dose 
9 Approximately 24 hours after the injection 
 
 
11 All screening laboratory results must be obtained before randomization to ensure participants eligibility 
 
12 In case of unscheduled visits for safety monitoring purposes during the time period from 4 hours to 24 hours after injection, unscheduled PK samples may be collected if operationally 
feasible. 
13 The outcome of this assessment will only be captured in the eCRF if amnesia is considered as an AE 


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8.1 
Screening 
Screening 
Investigators may re-screen a participant only once if the investigator is reasonably certain that 
reasons for screen failure will be resolved prior to or during a repeat screening attempt. Reasons 
to re-screen may include but are not limited to the following: 
• Laboratory value(s) out of range due to sampling error or that might be within range after 
medically-appropriate supplementation 
• The participant has a medical condition that can be stabilized or resolved prior to the 
repeat screening attempt 
• Additional time is required following the participant's last dose of an excluded medication 
(see Table 6-2) 
A participant must provide a new informed consent prior to the initiation of any re-screening 
procedures (e.g. participant must be reconsented). A new subject number will be assigned. 
8.1.1 
Eligibility screening 
8.1.1.1 
Hepatitis screen, HIV screen 
Not applicable. 
8.1.1.2 
Alcohol test, Drug screen, Urine cotinine 
Participants will be tested for substances of abuse (e.g. alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine and opiates). 
Positive results will not be exclusionary if the participant doesn’t meet DSM-5 criteria for 
substance use and inclusion would be the responsibility of the Investigator. 
This will be recorded as source data only by the use of an "S" for the corresponding criteria in 
Table 8-1 (Assessment Schedule) of the protocol. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an ICF and subsequently found to be ineligible prior to randomization 
will be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate CRF. The demographic information, informed consent, and the Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a SAE during screening phase (see SAE Section 10.1.3 for reporting details). If the participant 
fails to be randomized, the IRT must be notified within 2 days of the screen fail that the 
participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate CRF. 


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8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Participant demographic, socio-economical and baseline disease characteristic data will be 
collected on all participants. Relevant medical history/current medical conditions present prior 
to signing the informed consent will be recorded. Investigators have the discretion to record 
abnormal test findings on the medical history eCRF, if in their judgment, the abnormality 
occurred prior to the informed consent signature. 
Participant demographics: full date (if permitted) or year of birth, sex, race/predominant 
ethnicity (if permitted) and relevant medical history/current medical conditions (until date of 
signature of informed consent) will be recorded in the eCRF. Where possible, the diagnosis and 
not symptoms should be recorded. Participant race/ethnicity data are collected and analyzed to 
identify any differences in the safety and/or efficacy profile of the treatment due to these 
characteristics. In addition, we need to assess the diversity of the study population as required 
by Health Authorities. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 Concomitant Therapy 
for further details on what information must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy 
8.3.1 
Handling of Efficacy Assessments by Independent Site Raters 
The primary efficacy endpoint of MIJ821 compared with placebo is assessed based on the 
MADRS scale, SIGMA version. 
Administration of MIJ821 is associated with a number of transient adverse events, including 
sedation, dissociative symptoms, memory gaps/amnesia and cardiovascular events. To 
minimize the risk of introducing bias, trained and qualified site personnel will perform efficacy 
and safety assessments. Independent site raters who perform the MADRS, 
 
will be different from those who evaluate vital signs, adverse events, ECG results, MOAA/S, 
CADSS and C-SSRS. Independent site raters for the MADRS, 
 are not allowed 
to access or review participants safety records and, therefore, must not provide clinical care for 
participants. Clinical care of participants will be performed by the investigator or delegate at 
the study site who are not MADRS, 
 raters. 
Whenever possible, all efforts should be made to use the same independent raters for the 
MADRS, 
 at each site to assess the same participant throughout the study. If 
this is not possible, review of the appropriate prior assessments and communication with prior 
raters should be conducted, as needed. Any clinically relevant safety findings from the scales 
or the interviews must be communicated to the investigator. 
During the study, the roles of the investigator and the independent site rater, including their 
back-ups, are not interchangeable at the participating sites. 


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8.3.2 
Montgomery Asberg Depression Rating Scale (MADRS), SIGMA 
version 
The Montgomery Asberg Depression Rating Scale (MADRS, SIGMA version) 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. The MADRS evaluates apparent sadness, 
reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, 
pessimistic thoughts and suicidal thoughts (Khan et al 2002). The test exhibits high inter-rater 
reliability. In this study, the following recall periods will be used: “Last 7 days with euthymic 
baseline”, “over the past 4 hours”, "Last 7 days", and "Since last evaluation" for the primary 
endpoint. Whenever possible, the MADRS should be administered by the same rater to assess 
the same participant throughout the study. 
8.3.3 
Appropriateness of efficacy assessments 
The MADRS is a standard scale used for registration studies of depression. It is relatively quick 
to administer, does not focus predominately on the somatic symptoms of depression, but rather 
addresses core mood symptoms such as sadness, tension, lassitude, pessimistic thoughts, and 
suicidal thoughts. The MADRS is sensitive to change from treatment effects over time, and is 
considered a gold standard registration scale for depression.  
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every week or more frequently if needed) for safety 
monitoring and discussion of the participant´s health status until it is safe for the participant to 
visit the site again. 
Table 8-2 
Assessment Specification 
Assessment 
Specification 
Physical 
examination 
A complete PE will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed. A complete PE will be at 
screening and end of study visits. 
Information for all PEs must be included in the source documentation at the study site. 
Clinically relevant findings that are present prior to signing informed consent must be 
recorded on the appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an AE must be recorded as an 
AE. 


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Assessment 
Specification 
Vital signs 
Vital signs will include the collection of body temperature (recorded in °C), BP and pulse 
measurements and respiratory rate. Body temperature can be otic or oral according to local 
practice, but the same type of measurement should be used for the same participant at every 
assessment. 
After the participant has been resting in supine position for 5 minutes systolic and diastolic 
BP will be measured using an automated validated device with an appropriately sized cuff. In 
case the cuff sizes available are not large enough for the participant's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. BP will be measured 
following ECG measurements. Clinically notable values of BP or pulse (see Exclusion Criteria 
Section 5.2 and Section 3) need to be confirmed by a repeated measurement 2-5 minutes 
after the first measurement. 
In case of repeated vital assessments, the eCRF should contain all assessments at any time 
point (including screening, baseline and post-dose time points). 
Height and 
weight 
Height is obtained in centimeters (cm) and body weight is obtained in kilograms (kg) and 
rounded to the nearest 0.1 kg, and will be measured at screening and baseline. Weight is 
obtained in indoor clothing, without shoes, and repeated at baseline. 
8.4.1 
Laboratory evaluations 
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/eCRF page as appropriate. Clinically notable laboratory findings are defined in 
Appendix 1 (Section 16.1).  
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. 
In the case where a laboratory range is not specified by the protocol, but is outside the reference 
range for the laboratory at screening, a decision regarding whether the result is of clinical 
significance or not shall be made by the Investigator and shall be based, in part, upon the nature 
and degree of the observed abnormality. The assessment may be repeated once prior to 
randomization. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results should be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted. 
Fasting considerations: 
The participants must be fasting at screening in order to measure fasting glucose. In case the 
sample was not taken in a fasted state, a repeat sample should be taken at Day 1 after the 


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participant has been fasting overnight. For the subsequent visits, all participants must also be 
fasting overnight. If not, no repeat sample will be taken. 
Table 8-3 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hemoglobin, hematocrit, red blood cell count, white blood cell (WBC) count with 
differential (e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes), other 
(absolute value preferred and percent) and platelet count will be measured. 
Chemistry 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, calcium, Total cholesterol, low 
density lipoprotein (LDL), high density lipoprotein (HDL), chloride, creatinine (Glomerular 
Filtration Rate to be calculated based on the Cockcroft-Gault formula), creatinine kinase 
(CK), Gamma-glutamyl transferase (GGT), glucose (fasting), lactic dehydrogenase (LDH), 
phosphorus, lipase, amylase, magnesium, potassium, total protein, AST, ALT, sodium, 
triglycerides, blood urea nitrogen (BUN) or Urea, uric acid, C-reactive protein (high 
sensitivity). If the total bilirubin concentration is increased above 1.5 times the upper limit 
of normal, direct and indirect reacting bilirubin should be differentiated. 
Thyroid Stimulating Hormone (TSH) level will be analyzed as well. In case of clinically 
relevant abnormal TSH value, additional evaluation will be performed (free 
triiodothyronine [fT3] and free thyroxine [fT4]). 
Urinalysis 
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. A semi-
quantitative “dipstick” evaluation for the following parameters will be performed: specific 
gravity, pH, glucose, protein, bilirubin, urobilinogen, ketones, leukocytes and blood. If the 
dipstick result is positive for protein, leucocytes and/or blood, the sample will be sent for 
microscopic analysis of WBC, RBC and casts. Furthermore the protein-creatinine ratio 
(PCR) and the albumin-creatinine ratio (ACR) might also be measured 
Coagulation 
Prothrombin time/International normalized ratio (PT/INR), Activated partial thromboplastin 
time (APTT) 
Alcohol / Drugs of 
Abuse* 
Breathalizer / Dipstick 
Pregnancy Test 
and Assessment 
of Fertility 
Serum / Urine pregnancy test (as outlined in Section 8.4.3) 
* Since urine dipsticks are neither quantitative nor sensitive enough to detect the exact timeframe 
when a drug was used, if a urine dipstick result is positive for a drug(s) of abuse, the prohibited use (as 
defined in Section 6.2.1 and Section 6.2.2) should be further confirmed by the treating physician by 
means of a clinical assessment and data obtained from the participant or his/her relatives. The 
investigator judgment prevails in case of contradictory data or results. 
8.4.2 
Electrocardiogram (ECG) 
Figure 8-1 
Timing of study procedures 
 
Full details of all procedures relating to the ECG collection and reporting are contained in the 
technical manual provided by the core laboratory. 
ECGs must be recorded after the participant rests for 10 minutes, in supine position, to ensure 
a stable baseline and heart rate. Thereafter, three ECG should be taken at approximately 1 or 2-
minutes intervals (i.e., in triplicate) with ECG machines supplied by the core laboratory. The 


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preferred sequence of cardiovascular data collection during study visits is ECG collection first, 
followed by vital signs. The Fredericia QT correction formula (QTcF) must be used for clinical 
decisions. The investigator must calculate QTcF if it is not auto-calculated by the ECG machine. 
The mean QTcF value for each visit will be calculated from the triplicate ECGs for each 
participant. 
Triplicate 12 lead ECGs are to be collected with ECG machines supplied centrally. The ECGs 
must be reviewed by qualified site personnel in the first instance (e.g., cardiologist at site) and 
transmitted to the vendor as soon as possible after finishing the examination, for central review. 
The results of the centrally assessed ECGs will be electronically transferred into the clinical 
database. 
Any original ECG not transmitted to the vendor electronically should still be forwarded for 
central review. A copy of the ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. 
Clinically significant ECG abnormalities present prior to randomization should be reported on 
the Medical History CRF page. New or worsened clinically significant findings occurring after 
randomization must be recorded on the Adverse Events CRF page. 
A monitoring or review process should be followed for clinically significant ECG findings 
throughout the study and especially at baseline before administration of study treatment (see 
also Section 10.2.3 for details). 
8.4.2.1 
Cardiac imaging - MRA (magnetic resonance angiography), MUGA 
(multiple gated acquisition) scan or echocardiogram 
Not applicable 
8.4.2.2 
Cardiac enzymes 
Not applicable 
8.4.3 
Pregnancy and assessments of fertility 
Contraception 
During the study, investigators should ensure that study participants are regularly reminded of 
the importance of complying with the highly effective method of contraception, as it is 
applicable to them. 
Women of child-bearing potential (WOCBP), must use highly effective methods of 
contraception during dosing and for 1 week after stopping of investigational drug. For WOCBP, 
highly effective contraception methods include: 
• Total abstinence from heterosexual intercourse (when this is in line with the preferred and 
usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. 


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• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that participant. 
• Use of an intrauterine device (IUD) or intrauterine system (IUS). In case of use of an IUD 
or IUS, the device or system should have been placed and well tolerated by the patient for 
a minimum of 3 months before taking the study treatment  
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception other forms of hormonal contraception are not allowed for the purpose of 
contraception. 
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in the 
ICF. 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner while taking 
investigational drug and for 1 week after stopping study treatment. In addition, male participants 
should not donate sperm for the time period specified above. 
Pregnancy testing 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. See the 
Assessment schedule (Table 8-1), for timing of the protocol required pregnancy testing; 
additional pregnancy testing may be performed to meet local requirements.  In case of a positive 
urine pregnancy test at Baseline, study treatment must not be administered. 
Serum pregnancy testing will be conducted, unless specified otherwise. 
Refer to Section 10.1.4 for details on Reporting Pregnancy. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, luteinizing hormone (LH) and follicle 
stimulating hormone (FSH) testing is required of any female participant regardless of reported 
reproductive/menopausal status at screening. 


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8.4.4 
Safety evaluations related to mechanism of action of MIJ821 
To further assess safety events associated with the mode of action of MIJ821 in participants, 
the following assessments are to be conducted: 
• CADSS 
• MOAA/S 
• Memory assessment using orientation questions 
8.4.4.1 
Clinician-Administered Dissociative States Scale (CADSS) 
The CADSS is a questionnaire that assesses dissociative effects. Each item is scored from 0 to 
4 and individual scores are summed to obtain a total score ranging from a minimum of 0 to a 
maximum of 92. The trained staff administering the scale will also note their subjective 
interpretation of the participant's mental status and overall wellbeing, and whether any findings 
could be related to study drug. In this study, the following recall periods will be used: "current".  
The CADSS will be administered electronically by qualified site personnel according to 
Table 8-1.  
8.4.4.2 
Modified Observer's Assessment of Alertness/Sedation (MOAA/S) 
The purpose of this scale is to assess participant responsiveness on a scale from 0 (= Does not 
respond to painful trapezius squeeze) to 5 (= Responds readily to name spoken in normal tone 
[awake]). 
The MOAA/S will be administered electronically by qualified site personnel according to 
Table 8-1. 
8.4.4.3 
Memory Assessment using orientation questions 
Memory gaps/amnesia are AEs of Special Interest (AESI). Memory Assessment using 
orientation questions will be assessed by qualified personnel according to Table 8-1. 
Orientation questions will be asked to assess presence or absence of amnesia, as well as any 
distress for the participant, at defined intervals. The outcome of this assessment will only be 
captured in the eCRF if amnesia is assessed as an AE. In that case, the onset and resolution of 
amnesia should be identified as precisely as possible and these data will be recorded in the 
eCRF. While definite amnesia must be reported as an AE in the eCRF, possible mild amnesia 
may or may not be reported as an AE based on investigator judgment. 
8.4.5 
Oxygen saturation 
Pulse oximetry will be used to measure arterial oxygen saturation during the 4-hour observation 
period on the dosing day. The device will be attached to the finger, toe, or ear before study drug 
administration. Then, oxygen saturation will be monitored and documented in the source 
documents at site. Any arterial oxygen saturation (SpO2) <93% should be confirmed by an 
additional measurement on another part of the body. On the day of study drug administration, 
pulse oximetry will be recorded every 15 minutes starting from pre-dose until 4 hours post-
dose. If oxygen saturation levels are <93% at any time during the 4 hour postdose interval, pulse 


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oximetry will be recorded every 5 minutes until levels return to ≥ 93% or until the participant 
is referred for appropriate medical care, if clinically indicated. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for the study population and compounds with 
similar mechanism of action. As explained in Section 4.1.3, the safety assessments and their 
frequency were selected based on the completed FIH and PoC studies and the ongoing SAD 
study with s.c. MIJ821 in HVs. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
COA data may be collected remotely. 
8.5.1.1 
Clinician Reported Outcomes (ClinRO) 
ClinROs will be used to establish the diagnosis of depression and to assess and record the 
patient's treatment history at Screening. They will also be used to measure the impact of MIJ821 
on suicidality and disease severity with the following tools: 
• SCID-5 
• MGH-ATRQ 
• C-SSRS 
 
 
Structured Clinical Interview for DSM-5 (SCID-5) 
The SCID-5 is a semi-structured interview guide for DSM-5 disorders. It is administered by 
qualified personnel who are familiar with the DSM-5 classification and diagnostic criteria. The 
version used for this trial is the SCID-5-Clinical Trials version (SCID-5-CT). It guides the 
clinician step-by-step, through the DSM-5 diagnostic process, and allows to assess whether the 
diagnostic criteria have been met. Interview questions are provided along each corresponding 
DSM-5 criterion, which aids in rating each criterion as either present or absent. The SCID-5-
CT covers the DSM-5 diagnoses most commonly seen in clinical settings. 
The SCID-5-CT will be administered at screening only, as indicated in the Assessment Schedule 
Table 8-1. The SCID-5-CT responses will be recorded as source documentation only and will 
not be entered in the database. 
 










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The lesion size will be estimated and recorded as the largest diameter of the best fitted 
ellipsoidal form. Lesions will be graded as described below and recorded in the eCRF: 
• Mild lesion: 2.5-5 cm 
• Moderate lesion: 5.1-10 cm 
• Severe lesion: >10 cm 
9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from study treatment 
This is a single dose study, therefore treatment discontinuation for the individual participant is 
not applicable. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops further protocol-required 
assessments or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study or withdraw consent/oppose to the use of their 
data/biological samples, the investigator must show "due diligence" by documenting in the 
source documents steps taken to contact the participant, e.g. dates of telephone calls, registered 
letters, etc. A participant should not be considered as lost to follow-up until due diligence has 
been completed or until the end of the study. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 


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Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
No further assessments must conducted, and the data that would have been collected at 
subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 
9.3 
Study stopping rules 
Not applicable. 
9.4 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their End of Study visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation. 
9.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The investigator may be informed of 


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additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs 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. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2.  
1. The severity grade:  
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
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All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
6. Its outcome: recovery status or whether it was fatal 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued until EOS visit. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1. 
Dissociation and amnesia 
Dissociation means a lack of connection within or between oneself and one’s environment. It 
is not the same thing as “psychosis” which means fixed false beliefs (delusions) or false sensory 
experiences (hallucinations) but can be compared to the normal cognitive process of dreaming, 
where one is disconnected from one’s body and the real world. Déjà vu and déjà entendu are 
classic dissociative experiences. 
The two main forms of dissociation are depersonalization and derealization. In 
depersonalization one feels disconnected from oneself, whereas in derealization one feels 
disconnected from the world. This experience often is described as a sense of unreality, as if 
there was a film between oneself and one’s experience of the world. Dissociation is not the 
same as a hallucination, as there is no false sensory experience (e.g., hearing voices that do not 
exist). Rather normal sensory experiences occur as if they are not fully normal, as if there is 
some disconnection between the observer and the objects experienced. Depersonalization in 


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extreme cases may involve a feeling that one’s self is not one’s self, or that perhaps multiple 
selves can be identified in oneself. Dissociation can affect cognitive processes. One’s memories 
are not false, but they are remembered as if they are somehow not completely real. In severe 
cases, actual events may be forgotten. 
Amnesia means loss of memory. Dissociative amnesia means that things are not remembered 
because of dissociation, i.e., because of a sense of lack of connection between the self and the 
world. All other types of amnesia occur in settings where there is no dissociation. 
In assessing dissociative AEs or cognitive AEs of interest (such as amnesia or sedation), these 
AEs of special interest will be described in detail by participants and Investigators in writing in 
the source documents. The reported term should be as specific to the participant’s experience 
as possible. Investigators will record carefully the onset and resolution time of such AEs. Safety 
scales should be more frequently administrated every hour for the first 4 hours since the start of 
the event. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity  
• constitutes a congenital anomaly/birth defect 
• requires hospitalization or prolongation of existing hospitalization, unless hospitalization 
is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition of TRD 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 


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considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until EOS visit must be reported to Novartis safety 
immediately, without undue delay, under no circumstances later than within 24 hours of 
learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the electronic Serious Adverse Event (eSAE) with paper 
backup SAE Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. 
SAE reporting timeframes: 
1. SAEs occurring after the participant has provided informed consent until the time the 
participant is deemed a Screen Failure must be reported to Novartis. 
2. Randomized or Treated Participants: SAEs collected between time participant signs ICF 
until EOS visit. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 


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Any SAEs experienced after EOS visit should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 


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Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
 
 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1and Section 10.1.2). 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-2 in Appendix 2 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-2 should 
be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 16-3. 
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation. 
These liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should have 
results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated. 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease  
• Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
• Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
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• Exclusion of underlying liver disease, as specified in Appendix 2 (Section 16.2) 
• Imaging such as abdominal ultrasound, computerized tomography, or magnetic 
resonance imaging, as appropriate 
• Obtaining a history of exposure to environmental chemical agents. 
• Considering gastroenterology or hepatology consultations. 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.2 
Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• Any one of the following:  
• Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR 
• New onset dipstick proteinuria ≥ 3+, OR 
• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, Urinary Tract 
Infection (UTI), extreme exercise, or trauma) 
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment.  
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff as summarized 
in Appendix 3 (Section 16.3). 
Every renal laboratory trigger or renal event as defined in Table 16-5 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-6. 
10.2.3 
Cardiac Monitoring 
To ensure participant safety cardiac monitoring has to be followed for all participants. 
Please refer to Section 16.4 and Table 16-1 for clinically notable vital signs and ECG alert 
threshold values. 
Post dose cardiac monitoring: 
Every clinically significant cardiac event should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. 
• If the initial abnormality is confirmed, close observation of the participant can be initiated 
based on investigator’s discretion 
• Causality assessment of the cardiac event should be evaluated 
• Thorough follow-up of the cardiac event. These investigations can include based on 
investigator’s discretion: increasing the cardiac monitoring level; initiating additional 
diagnostic or therapeutic procedures to ensure patient safety, and to better characterize the 
finding and/or its cause; consultancy with a cardiologist 
• Hospitalization of the participant if appropriate 


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Post dose QT prolongation: 
In case of a clinically significant postdose QT prolongation, in addition to the abovementioned 
cardiac monitoring measures, the following additional measures are recommended 
• Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study treatment. 
Post dose blood pressure monitoring: 
The following monitoring criteria based on post-dose blood pressure assessments during the 
dosing phase should be followed: 
At 1.5 hours post-dose, if the SBP is ≥160 mmHg and/or the DBP ≥100 mmHg, assessments 
should continue every 30 minutes until: 
• The blood pressure is <160 mmHg SBP and <100 mmHg DBP, or 
• In the investigator’s clinical judgment, the subject is clinically stable or 
• The subject is referred for appropriate medical care, if clinically indicated 
• If the blood pressure remains ≥ 160 mmHg SBP and/or / ≥100 mmHg DBP, 4 hours after 
dosing, the subject should be referred for immediate medical treatment. 
For participants with SBP ≥180 mmHg but <200 mmHg and/or the DBP is ≥110 mmHg but 
<120 mmHg participant should be referred to a cardiologist, or other specialist for a follow-up 
assessment. 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.4 
Prospective suicidality assessment 
The C-SSRS is a questionnaire that prospectively assesses suicidal ideation and suicidal 
behavior. The C-SSRS must be administered as defined in the Visit schedule (Section 8). 
The C-SSRS, which uses a semi-structured interview to probe participant responses, will be 
administered by an individual who has received training and certification in its administration. 
At the first study visit, the “baseline/screening” version of the C-SSRS will be administered. 
This version assesses suicidal ideation and suicidal behavior during the participant's last one 
year and during a predefined period of one month. At subsequent visits, the “since last visit” 
version will be administered. 
If, at any time after screening and/or baseline (i.e., prior to randomization), the score is “yes” 
on item 4 or item 5 of the suicidal ideation section of the C-SSRS or “yes” on any item of the 
suicidal behavior section, the participant should be screened failed and adequate treatment and 
management should be provided as per standard of care. 
In addition, all life-threatening events must be reported as SAEs. For example, if a participant 
answers “yes” to one of the questions in the suicidal behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the suicidal behavior section) should be reported as AEs and assigned 
the appropriate severity grade. 


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10.2.5 
Adverse events of special interest 
Based on the current available information, considering the ketamine safety profile and 
clinical/non-clinical evidence available for MIJ821, following events are considered AESI. This 
information is subject to change, based on the availability of incremental clinical experience 
with MIJ821. Please refer to the current Investigator Brochure for the most updated information 
on safety profile. 
• Dissociation 
• Sedation 
• Cardiovascular effects (BP changes and QT interval prolongation on ECG) 
• Respiratory effects (difficulty in breathing, changes in oxygen saturation) 
• Suicidality (suicidal ideation or behavior) 
• Memory gaps/ amnesia 
• Cystitis or lower urinary tract adverse events 
The list of current adverse events of special interest is available in the IB. 
Post dose observation / Hospitalization 
A four-hour post-dose observation period is implemented in this trial to ensure patients’ safety 
and give required time for the potential events of interest to onset. Most of the events of interest 
should also be resolved by the end of the suggested observation period. The adverse events of 
interest should be followed up on site until resolution or until absence of safety risk assessed by 
the investigator based on clinical evaluation and judgement. If severe dissociative, psychotic, 
suicidal, sedative, cardiovascular or agitated symptoms emerge, it is recommended 
investigators hospitalize participants until those adverse events are resolved. If they persist, or 
based on clinical judgment or patient preference, those participants can be discontinued from 
the study at any time. 
In case of a safety concern or worsening of depressive symptoms including suicidal ideation, 
participants' hospitalization should be prolonged or they can be re-hospitalized at any timepoint 
of the study overnight or for a longer period until they improve clinically, as per investigator 
clinical judgement. If suicidal symptoms are present to a moderate to severe degree, either based 
on rating scales or investigator judgment, and such symptoms persist throughout the above 
mentioned monitoring period following the intravenous infusion, investigators must hospitalize 
participants at least overnight. If suicidal symptoms are mild, either based on rating scales or 
investigator judgment, the investigator's judgment can be used to allow the participant to leave 
the clinical setting, but in that case arrangements should be made such that family members or 
friends are present with the participant for at least 24 hours. If such arrangements cannot be 
made, it is recommended that the participant is hospitalized at least overnight. 
Caution with performance of potentially dangerous tasks  
Given that MIJ821 may impair the mental or physical abilities required for the performance of 
potentially dangerous tasks such as driving a car or operating machinery, participants should be 
advised about these potential risks. If the participant is feeling drunk or dizzy or if he/she 
experiences visual disturbances, hallucinations, or euphoric mood, then he/she should not drive, 
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In case of a safety concern, the participant should be hospitalized (or hospitalization should be 
prolonged) as per investigator's judgement until resolution of these events or absence of a safety 
risk. 
Scales / tools to assess CNS related AEs 
Additional scales have been implemented to assess events of sedation (MOAA/S), dissociation 
(CADSS) and C-SSRS scale will be used for assessment of suicidality. Investigators will be 
trained specifically on identification and appropriate recording of amnesia. Diagnosis of 
amnesia will be sought by detailed clinical evaluation of the participants (e.g. orientation 
questions, memory assessment questions, exclusion of other diagnosis, in conjunction with 
dissociation, categorisation of retrograde or anterograde amnesia, time to onset and time to 
resolution). In case of clinically significant findings or changes observed during the 
administration of the scales, it is recommended that an adverse event or SAE be recorded as 
appropriate. 
See also sections Section 6.2.3, Section 9.1.1, and Section 10.2.4 for additional details. 
Cardiovascular AEs 
For cardiovascular effects, specifically for blood pressure increase, unless clinically indicated, 
it is recommended that transient increases in blood pressure not be treated, as the blood pressure 
typically returns to pre-dose values in 3-4 hours. In case of clinically notable values for vital 
signs as defined in Section 16.1, a treatment may be considered as per clinical judgement of the 
investigator. See also Section 10.2.3 for additional guidance. 
10.3 
Committees 
10.3.1 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, review unblinded safety data, and critical efficacy variables and recommend 
to the sponsor whether to continue, modify, or terminate a trial. 
The study may be put on hold and no further enrollment will take place pending full safety data 
review in case any significant safety finding(s) are observed by the DMC. In case of the study 
being put on hold, Novartis will promptly notify all concerned investigators/institutions, Ethics 
Committees/Review Boards and the Regulatory Authorities. The findings and the 
recommendations of the DMC will be documented and will be made available in the respective 
Ethics Committees/Review Boards and the Regulatory Authorities.  
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
10.3.2 
Steering Committee 
The Steering Committee (SC) is established as a group of external experts in the fields of 
psychiatry with profound knowledge and experience including clinical research in major 


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depression. These experts may participate in this trial as investigators, but will not be members 
of the DMC and Novartis representatives from the Clinical Trial Team (CTT). 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the CTT, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the steering committee will be defined in the steering committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1) and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 


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adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis (or 
a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits.  Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the participant's file. Data 
not requiring a separate written record will be defined before study start and will be recorded 
directly on the CRFs. The investigator must also keep the original ICF signed by the participant 
(a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 


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12 
Data analysis and statistical methods 
The primary analysis will be performed at the End of Study. The efficacy will be tested and the 
dose-response relationship will be established based on the primary estimand by method of 
Multiple Comparison Procedure-Modeling (MCP-Mod). 
Summary statistics will be presented by treatment group unless otherwise specified. For 
continuous variables, summary statistics will generally include: n, mean, standard deviation 
(SD), median, quartiles, minimum and maximum. For categorical variables, this will generally 
include: frequency and percentage in each category. Further technical details and discussions 
of statistical considerations will be provided in the Statistical Analysis Plan (SAP). 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all randomized participants who received a dose of the 
randomized treatment. Participants will be analyzed according to the study treatment received. 
The Safety Set includes all participants who received any study drug. Participants will be 
analyzed according to the study treatment received. 
The PK analysis set will include all participants with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized and 
combined by system organ class and by treatment. 
12.3 
Treatments 
The Safety set will be used for the analyses below.  
Data for study drug administration will be summarized by treatment group. 
Concomitant medications will be summarized according to the Anatomical Therapeutic 
Chemical (ATC) code, preferred term and treatment group. Prohibited and rescue medication 
will be analyzed similarly. Significant non-drug therapies will be summarized by SoC, preferred 
term and by treatment group. 
Total duration of time in study and reasons for discontinuation from study will be summarized 
by treatment group. 


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All available data under safety analysis set will be used for reporting purpose. 
12.4 
Analysis supporting primary objectives 
The primary clinical question of interest is: What is the effect of s.c. MIJ821 versus placebo in 
addition to SoC at 24 hours after the injection of the study drugs on change in depressive 
symptoms measured by MADRS total score in participants with treatment resistant depression 
(TRD), who have already failed to adequately respond to at least two conventional 
antidepressants, while accounting for intercurrent events (IEs) with potential confounding 
effects and IEs leading to study discontinuation prior to 24 hours? 
This section describes the primary analysis for the primary estimand. The related sensitivity 
analyses and supportive analysis will be detailed in the statistical analysis plan (SAP). 
12.4.1 
Definition of primary endpoint(s) 
The primary estimand is described by the following attributes: 
1. Population: participants with treatment resistant depression, who have failed to show 
adequate treatment response to at least 2 antidepressants previously. 
2. Primary variable: change from baseline to 24 hours post dose in the MADRS total score 
3. Treatment of interest: the randomized treatment (the investigational treatment MIJ821 or 
the placebo treatment) administered as a single s.c. injection on Day 1. The dose of the 
allowed concomitant medication (SoC) for depression must remain stable after baseline 
and during the trial. 
4. Intercurrent Events (IEs) prior to MARDS assessment at 24 hours (see Section 12.4.3 for 
more details): 
IEs with potential confounding effect prior to the 24-hour assessment: 
• New intake or change in concomitant medications/therapies which have a potential 
confounding effect 
• Intake of prohibited medications/therapies 
• Intake of rescue medication 
• Pandemic related IEs 
Participants who took prohibited medications/therapies, rescue medications, or took new or 
change concomitants medications/therapies which have potential confounding effect, will 
continue in the study and be assessed as scheduled. 
IEs leading to study discontinuation prior to the 24 hour assessment: 
• Adverse events (AE) 
• Lack of efficacy (LoE) 
• Other reasons for study discontinuation 
The summary measure: treatment difference in variable means between study drug and placebo. 


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12.4.4 
Handling of missing values not related to intercurrent event 
Imputation of intermittent missing observations will be carried out following a MAR 
mechanism for all treatment arms. 
 
 
 
 
 
 


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12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Duration of antidepressant effect of MIJ821 
To assess the efficacy of antidepressant effect of MIJ821 over time, the following secondary 
endpoints will be evaluated: 
• The change from baseline in the total MADRS score at Day 2, 8, 15, 22 and Day 29 visits 
after s.c. administration will be analyzed using the mixed-effect model for repeated 
measures (MMRM). This model will include the fixed, categorical effects of treatment, 
time (i.e. analysis visits), baseline MADRS score, class of anti-depressant standard of 
care, treatment-by-time and baseline MADRS score-by-time interactions. An unstructured 
(UN) covariance structure will be used to model the within-subject variability. More 
details of this analysis will be specified in SAP. 
• Number (percentage) of participants who discontinued study due to lack of efficacy or 
need for new antidepressant treatment (pharmacological or psychotherapy) will be 
summarized by treatment arms. 
Dose-response relationship of MIJ821 
The assessment for the dose-response relationship of MIJ821 and estimation of the target dose 
will be based on the estimated dose-response curve derived from the MCP-Mod methodology 
in primary analysis (see Section 12.4.2). 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period will be defined as starting from the date of administration of study 
treatment plus up to EOS visit. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and 
participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the study medication or events present prior to start of double-blind treatment but 
increased in severity based on preferred term) will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term. 


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• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
The number (and percentage) of psychotomimetic AEs (dissociation, amnesia, sedation) will 
be tabulated by treatment group, according to severity and relationship to drug. 
The number (and percentage) of participants with adverse event of special interest (AESI) will 
be summarized by treatment. AESI include risks specified in the safety profiling plan or any 
other events of interest specific to the project. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged.  
Summary statistics will be provided by treatment group and visit/time. The average blood 
pressure change over time will be presented by line plot. 
12-lead ECG 
All ECG data will be listed by treatment group, subject and visit/time; abnormalities will be 
flagged. 
The overall interpretation of the ECGs will be summarized by treatment group and visit/time. 
Any clinically significant changes in ECG parameters will be summarized by treatment group. 
Summary statistics will be provided by treatment and visit/time.  
Clinical laboratory evaluations 
Notable abnormal laboratory data will be listed by treatment group, participant and visit if 
ranges are available. 
All laboratory data will be summarized by treatment group, and visit/time. Shift tables using 
the low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value.  
12.5.3 
Pharmacokinetics 
MIJ821 plasma concentrations will be expressed in mass per volume. The plasma 
concentrations will be listed by treatment/dose, subject number, and visit/sampling time point. 
Descriptive summary statistics of plasma concentrations will be provided by treatment/dose and 
visit/sampling time point including the frequency (n, %) of concentrations below the LLOQ and 
reported as zero. Summary statistics of plasma concentrations will include arithmetic and 
geometric mean, SD, and CV and median, minimum, and maximum. Concentrations below 




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12.5.6 
PK/PD relationships 
The exposure response relationship will be presented graphically for PK exposure parameters 
(e.g. Cmax and AUClast) and the MADRS score change from baseline at 24 h after s.c. 
injection. Correlations will be assessed using statistical analysis methods (e.g. trendline analysis 
methods) or simple exposure response models (e.g. Emax models) if data allows. Details are 
described in the Statistical Analysis Plan. 




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results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter - at study completion/last visit 
• Plain language trial summary - after CSR publication 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
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14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
(2021) FDA-Approved Drugs to Treat Major Depressive Disorder (MDD). J Psychosoc Nurs 
Ment Health Serv; 59(7):5-6. 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics; 61(3):738-48. 
Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-
acting novel antidepressants. Front Pharmacol p 161. 
EMA (2015) Report from Dose Finding Workshop. European Medicines Agency, London, 04 
– 05 December 2014. 
Gelenberg AJ, Freeman MP, Markowitz JC et al (2010) Practice guideline for treatment of 
patients with major depressive disorder. Third edition. p. 1-118. 
Guy (1976) ECDEU assessment manual for psychopharmacology (Internet) Accessed from:  
(Accessed 25-Mar-2022) 
Ibrahim L, Diaz Granados N, Jolkovsky L, et al (2012) A Randomized, placebo-controlled, 
crossover pilot trial of the oral selective NR2B antagonist MK-0657 in patients with 
treatment-resistant major depressive disorder. J Clin Psychopharmacol; 32(4):551-7. 
Katalinic (2013) Ketamine as a new treatment for depression: A review of its efficacy and 
adverse effects; Australian & New Zealand Journal of Psychiatry; 47(8):710-27 
Khan A, Khan SR, Shankles EB, et al (2002) Relative sensitivity of the Montgomery-Asberg 
Depression Rating Scale, the Hamilton Depression rating scale and the Clinical Global 
Impressions rating scale in antidepressant clinical trials. Int Clin Psychopharmacol p. 281-5. 
Kirsch I (2019) Placebo Effect in the Treatment of Depression and Anxiety. Front Psychiatry; 
10:407. 
Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to 
change. Brit J Psychiat; 134:382-9. 
Preskorn SH, Baker B, Kolluri S, et al (2008) An innovative design to establish proof of 
concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate 
antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin 
Psychopharmacol; 28(6):631-7. 
Rush AJ, Trivedi MH, Wisniewski SR, et al (2006) Acute and longer-term outcomes in 
depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J 
Psychiatry; 163(11):1905-17. 
Sackeim HA (2001) The definition and meaning of treatment-resistant depression. J Clin 
Psychiatry; 16:10-7. 
Shelton RC, Osuntokun O, Heinloth AN, et al (2010) Therapeutic options for treatment-
resistant depression. CNS Drugs; 24(2):131-61. 


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WHO (2020) World Health Organization: Depression (Depression. Key facts) (Internet) 
Available from:  (Accessed 25-Mar-2020) 
https://crediblemeds.org/ 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values and vital signs 
Table 16-1 
16-1 Clinically notable values for vital signs 
Variable 
Criterion value 
Change relative to baseline 
Heart rate/pulse 
≥120 bpm; ≤50 bpm 
increase of ≥ 15 bpm decrease of ≥ 15 bpm 
Systolic blood pressure 
≥180 mm Hg; ≤90 mm Hg 
increase of ≥ 20 mm Hg decrease of ≥ 20 mm Hg 
Diastolic blood pressure 
≥105 mm Hg; ≤50 mm Hg 
increase of ≥ 15 mm Hg decrease of ≥ 15 mm Hg 
bpm= beats per minute 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-2 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin 
normal at baseline: 
● ALT or AST > 5 × upper limit of normal (ULN) 
● ALP > 2 × ULN (in the absence of known bone pathology) 
● Total bilirubin > 3 × ULN (in the absence of known Gilbert syndrome) 
● ALT or AST > 3 × ULN and INR > 1.5 
● Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and Total 
bilirubin > 2 × ULN [mainly conjugated fraction] without notable increase in 
ALP to > 2 × ULN) 
● Any clinical event of jaundice (or equivalent term) 
● ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
● Any adverse event potentially indicative of a liver toxicity* 
If ALT or AST abnormal at 
baseline: 
● ALT or AST > 2x baseline or > 200 U/L (whichever occurs first) 
* These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms upper 
limit of normal 
Table 16-3 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
  
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
None 
● Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 
  
If normal at 
baseline: 
Normal 
None 
● Measure ALT, 
AST, ALP, GGT, 


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ALT 
TBL 
Liver Symptoms 
Action 
ALT > 5 x ULN for 
more than two 
weeks 
For participants 
with Gilbert’s 
syndrome: No 
change in baseline 
TBL 
TBIL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
● Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
If elevated at 
baseline: 
ALT > 3 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than 
two weeks 
  
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or 
INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 
  
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 
Table 16-4 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Biliruin (isolated) 
  
  
>1.5 – 3.0 ULN 
● Repeat LFTs within 48-72 hours 
Monitor LFTs weekly until resolution* to ≤ 
Grade 1 or to baseline 
> 3 - 10 × ULN (in the 
absence of known Gilbert 
syndrome) 
● Repeat LFT within 48-72 hours 
● Hospitalize if clinically appropriate 
● Establish causality 
● Record the AE and contributing 
factors (e.g. conmeds, med hx, lab) 
in the appropriate CRF 
Monitor LFTs weekly until resolution to ≤ 
Grade 1 or to baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
● Hospitalize the participant 
● Establish causality 
● Record the AE and contributing 
factors(e.g. conmeds, med hx, 
lab)in the appropriate CRF 
ALT, AST, total bilirubin, Alb, PT/INR, 
ALP and GGT until resolution* (frequency 
at investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
Any AE potentially 
indicative of a liver toxicity 
● Hospitalization if clinically 
appropriate 
● Establish causality 
● Record the AE and contributing 
factors(e.g., conmeds, med hx, 
lab)in the appropriate CRF 
Investigator discretion 
* Resolution is defined as an outcome of one of the following: (1) return to baseline value, (2) stable 
value at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death  
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 
16.3 
Appendix 3: Specific Renal Alert Criteria and Actions and Event 
Follow-up 
Table 16-5 
Specific Renal Alert Criteria and Actions 
Renal Event 
Actions 
Confirmed serum creatinine increase 25 – 
49% 
● Consider causes and possible interventions 
● Follow up within 2-5 days 
Serum creatinine increase ³ 50 % + 
● Consider causes and possible interventions 
● Repeat assessment within 24-48h if possible 
● Consider participant hospitalization and specialized treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 
● Consider causes and possible interventions 
● Assess serum albumin & serum total protein 
● Repeat assessment to confirm 
New onset hematuria ≥ 3+ on urine dipstick 
● Repeat assessment to confirm 
● Distinguish hemoglobinuria from hematuria 
● Urine sediment microscopy 
● Assess sCr 
● Exclude infection, trauma, bleeding from the distal urinary 
tract/bladder, menstruation 
● Consider bleeding disorder 
Additional specialized assessments are available to assess renal function or renal pathology. 
Whenever a renal event is identified, a detailed participant history and examination are indicated 
to identify and potentially eliminate risk factors that may have initiated or contributed to the 
event: 
• Blood pressure assessment (after 5-minute rest, with an appropriate cuff size 
• Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edem 
• Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine outpu 


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• Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis 
Table 16-6 
Follow-up of renal events 
FOLLOW-UP OF RENAL EVENTS 
Assess, document and record in CRF 
● Urine dipstick and sediment microscopy evidence of DIN:  crystals, red blood cells (dysmorphic/glomerular 
vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cell 
● Blood pressure and body weigh 
● Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric aci 
● Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) in the CRF 
Monitor participant regularly (frequency at investigator’s discretion) until - 
● Event resolution: sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr o 
● Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio stabilization 
at a new level with ±50% variability over last 6 months 
● Analysis of urine markers in samples collected over the course of the DIN event 
16.4 
Appendix 4: ECG Alert Threshold Values 
  
Patients 18-30 years 
Patients Adult > 30 years * 
Resting heart rate Sinus rhythm 
[bpm] 
HR < 30 and a HR decrease ≥ 
25% HR > 130 
HR < 40 and a HR decrease ≥ 
25% HR > 120 
QRS duration: 
  
  
=> No previous BBB ** 
> 120 and increase > 25% 
compared to (predose) baseline 
> 120 and increase > 25% 
compared to (predose) baseline 
=> Previous complete BBB * (>120 
msec) 
> 140 msec 
> 140 msec 
QTcF 
QTcF > 500 msec QTcF 
increase > 60 msec *** 
QTcF > 500 msec QTcF 
increase > 60 msec *** 
Rhythm 
Ventricular tachycardia 
Ventricular tachycardia 
Conduction 
New complete heart block (Grade 
III AV block) Mobitz II AV block 
New complete heart block (Grade 
III AV block) Mobitz II AV block 
* Values displayed also correspond to Severe AE ** BBB = Bundle Branch Block *** Normal QTcF with QTc 
increase > 60 ms may indicate cardiac and non-cardiac pathology, e.g. hypothermia, new BBB, MI. 
cardiomyopathy or carditis. 
16.5 
Appendix 5: Medications with a Known Risk of Torsades de 
Pointes 
Table 16-7 
Medications with a Known Risk* of Torsades de Pointes 
Generic name 
Brand name 
TdP Risk 
Aclarubicin 
Aclacin and others 
known 
Amiodarone 
Cordarone and others 
known 
Anagrelide 
Agrylin and others 
known 
Arsenic trioxide 
Trisenox 
known 
Astemizole 
Hismanal 
known 


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Generic name 
Brand name 
TdP Risk 
Azithromycin 
Zithromax and others 
known 
Bepridil 
Vascor 
known 
Cesium Chloride 
Energy Catalyst 
known 
Chloroquine 
Aralen 
known 
Chlorpromazine 
Thorazine and others 
known 
Chlorprothixene 
Truxal 
known 
Cilostazol 
Pletal 
known 
Ciprofloxacin 
Cipro and others 
known 
Cisapride 
Propulsid 
known 
Citalopram 
Celexa and others 
known 
Clarithromycin 
Biaxin and others 
known 
Cocaine 
Cocaine 
known 
Disopyramid 
Norpace 
known 
Dofetilide 
Tikosyn 
known 
Domperidone 
Motilium and others 
known 
Donepezil 
Aricept 
known 
Dronedarone 
Multaq 
known 
Droperidol 
Inapsine and others 
known 
Erythromycin 
E.E.S. and others 
known 
Escitalopram 
Cipralex and others 
known 
Flecainide 
Tambocor and others 
known 
Fluconazole 
Diflucan and others 
known 
Gatifloxacin 
Tequin 
known 
Grepafloxacin 
Raxar 
known 
Halofantrine 
Halfan 
known 
Haloperidol 
Haldol and others 
known 
Hydroquinidine (Dihydroquinidine) 
Serecor 
known 
Hydroxychloroquine 
Plaquenil and others 
known 
Ibogaine 
  
known 
Ibutilide 
Corvert 
known 
Levofloxacin 
Levaquin and others 
known 
Levomepromazine (Methotrimeprazine) 
Nosinan and others 
known 
Levomethadyl acetate 
Orlaam 
known 
Levosulpiride 
Lesuride and others 
known 
Mesoridazine 
Serentil 
known 
Methadone 
Dolophine and others 
known 
Moxifloxacin 
Avelox and others 
known 
Nifekalant 
Shinbit 
known 
Ondansetron 
Zofran and others 
known 
Oxaliplatin 
Eloxatin 
known 
Papaverine HCl (Intracoronary) 
  
known 
Pentamidine 
Pentam 
known 
Pimozid 
Orap 
known 
Probucol 
Lorelco 
known 
Procainamide 
Pronestyl and others 
known 
Propofol 
Diprivan and others 
known 


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Generic name 
Brand name 
TdP Risk 
Quinidine 
Quinaglute and others 
known 
Roxithromycin 
Rulide and others 
known 
Sevoflurane 
Ultane and others 
known 
Sotalol 
Betapace and others 
known 
Sparfloxacin 
Zagam 
known 
Sulpiride 
Dogmatil and others 
known 
Sultopride 
Barnetil and others 
known 
Terfenadine 
Seldane 
known 
Terlipressin 
Teripress and others 
known 
Thioridazine 
Mellaril and others 
known 
Vandetanib 
Caprelsa 
known  
* This is a non-exhaustive list, updated information are listed in www.qtdrugs.org 
16.6 
Appendix 6: Antidepressants recommended to be used as 
background therapy during the study 
 
Generic Name 
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) 
Fluoxetine  
Fluoxetine delayed release 
Paroxetine  
Paroxetine controlled release 
Sertraline 
SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) 
Desvenlafaxine  
Desvenlafaxine Extended 
 Release  
Duloxetine  
Levomilnacipran 
Venlafaxine 
NOREPINEPHRINE–DOPAMINE REUPTAKE INHIBITORS 
Bupropion  
SEROTONIN NOREPINEPHRINE RECEPTOR AGONISTS 
Mirtazapine  
SEROTONINE 2 ANTAGONIST/ REUPTAKE INHIBITORS 
Trazodone* 
MULTIMODAL ANTIDEPRESSANT/MULTIPLE SEROTONERGIC ACTIONS 
Vilazodone  
Vortioxetine  
TRICYCLIC ANTIDEPRESSANTS 
Amitripthyline* 
Amoxapine  
Desipramine  
Doxepin  
Imipramine 
Nortriptyline* 


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Protriptyline  
Trimipramine 
Table adapted from FDA Approved Drugs to Treat Major Depressive Disorder (MDD). 2021 
* Ensure that the prohibited time window before and after study drug injection is respected, as 
indicated in Table 6-2 (Prohibited Medications and Treatment) 
 

SAP_001.pdf: 








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2.7.3 
Laboratory data ..................................................................................... 30 
2.7.4 
Other safety data ................................................................................... 31 
2.8 
Pharmacokinetic endpoints .................................................................................... 34 
2.8.1 
Variables ............................................................................................... 34 
2.8.2 
Descriptive analyses .............................................................................. 34 
 
 36 
2.9 
PD and PK/PD analyses ........................................................................................ 37 
 
 37 
 
 37 
 
 38 
2.13 
Interim analysis ...................................................................................................... 40 
3 
Sample size calculation ..................................................................................................... 40 
4 
Change to protocol specified analyses .............................................................................. 40 
5 
Appendix ........................................................................................................................... 41 
5.1 
Imputation rules ..................................................................................................... 41 
5.1.1 
Study drug ............................................................................................. 41 
5.1.2 
AE date imputation ............................................................................... 41 
5.1.3 
Concomitant medication date imputation ............................................. 41 
5.1.4 
Baseline SoC categories ........................................................................ 41 
5.2 
AEs coding/grading ............................................................................................... 41 
5.3 
Laboratory parameters derivations ........................................................................ 41 
 
 43 
 
 43 
 
 44 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 47 
6 
Reference ........................................................................................................................... 47 
 
List of tables 
Table 1-1 
Study objectives and related endpoints ................................................. 10 
Table 2-1 
Analysis visit windows (except for Lab and ECG) ............................... 15 
Table 2-2 
Analysis visit windows for Laboratory ................................................. 15 
Table 2-3 
Analysis visit windows for ECG ........................................................... 15 
 
 21 
 
 25 
Table 2-6 
AE summaries ....................................................................................... 28 


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Table 2-7 
Safety disclosure requirements ............................................................. 29 
Table 2-8 
Criteria for newly occurring or worsening laboratory parameters ........ 30 
Table 2-9 
CADSS components and total scales .................................................... 32 
Table 2-10 
C-SSRS components ............................................................................. 33 
Table 5-1 
Liver abnormality criteria ..................................................................... 42 
Table 5-2 
Renal abnormality criteria ..................................................................... 43 
Table 5-3 
Clinically notable values for vital signs ................................................ 43 
Table 5-4 
ECG abnormality criteria ...................................................................... 43 
Table 5-5 
Participants classification ...................................................................... 47 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
 
 24 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical classification 
CADSS 
Clinician-Administered Dissociative States Scale 
 
 
 
  
CRF 
Case Report Form 
CRS 
Case Retrieval Strategy  
CS 
Compound Symmetry  
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CT.GOV 
ClinicalTrials.gov 
CTCAE 
Common Terminology Criteria for Adverse Events  
DMC 
Data Monitoring Committee 
DMS 
Document Management System 
DR 
Dose Response 
 
  
 
  
EOS 
End of Study 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full Analysis Set  
FWER 
Family-wise Error Rate 
IA 
Interim Analyses 
IE 
Intercurrent Events  
IRT 
Interactive Response Technology 
 
  
LoE 
Lack of efficacy  
LS-means 
Least Squares Means  
 
  
MADRS 
Montgomery Asberg Depression Rating Scale 
MAR 
Missing at Random  
 
 
 
 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MI 
Multiple Imputation  
MMRM 
Mixed-effects Model for Repeated Measures  
MNAR 
Missing Not at Random  
MOAA/S 
Modified Observer's Assessment of Alertness/Sedation 
PD 
Protocol Deviations  
PDS 
Programming Dataset Specification  


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PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
 
 
PT 
Preferred Term 
RAP 
Reporting & Analysis Process 
s.c. 
subcutaneous 
SAE 
Serious Adverse Events  
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query 
SNRI 
Serotonin–Norepinephrine Reuptake Inhibitor 
SoC 
Standard of Care 
SOC 
System Organ Class 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TEAE 
Treatment-emergent Adverse Events 
TFLs 
Tables, Figures, Listings 
TRD 
Treatment Resistant Depression 
WHO 
World Health Organization 
 


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1 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical analysis 
described in [Section 12] of the Protocol v02 (release date: 04-Nov-2022) for study 
CMIJ821B12201. 
This SAP includes the detailed plans for the primary, secondary 
 objectives 
of the study as well as supplementary analyses for the primary objective and associated 
sensitivity analyses. All the statistical analysis results based on this SAP will be reported in the 
final Clinical Study Report (CSR). The analysis mentioned in this SAP will be performed by 
Novartis internal statisticians and programmers, if not specified differently.  
1.1 
Study design 
This is a Phase IIa non-confirmatory, randomized, double-blind, placebo-controlled, parallel-
group trial in participants with Treatment-Resistant Depression (TRD) to evaluate the efficacy, 
safety, tolerability, and pharmacokinetics of subcutaneous (s.c.) MIJ821 administration in 
addition to pharmacological antidepressant standard of care (SoC) treatment. The study design 
is illustrated in Figure 1-1. 
Participants will be randomly allocated to one of the following four treatment arms in a 1:1:1:1 
ratio: 
• Single administration of MIJ821 s.c. 10 mg; 
• Single administration of MIJ821 s.c. 4 mg; 
• Single administration of MIJ821 s.c. 1 mg; 
• Single administration of Placebo s.c.. 
The screening period starts when the participant signs the informed consent form and can last 
up to 28 days. The eligibility of participants is determined based on the assessments performed 
during the screening period and also on Day 1 (baseline/ prior to randomization).  
Approximately 56 participants will be randomized to one of the above treatment arms via 
Interactive Response Technology (IRT) on Day 1/pre-dose in a blinded manner. The 
randomization will be stratified by the class of baseline anti-depressant SoC, which includes 
three categories: i) Selective Norepinephrine Reuptake Inhibitors (SNRI); ii) Selective 
Serotonin Reuptake Inhibitors (SSRI) and iii) other anti-depressants or any combinations. 
In all treatment arms, the investigational treatment (MIJ821 or Placebo) is administered as a 
single s.c. injection on Day 1, followed by a safety observation at the clinical site for a minimum 
of 4 hours after administration. Details of the safety assessments and release criteria can be 
found in the protocol. 
The post-dose follow-up period will continue for 4 weeks (28 days) after treatment. On-site 
visits to assess efficacy and safety are scheduled on Day 2 (24 hours post-dose) and 




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Objective(s) 
Endpoint(s) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To assess safety and tolerability of MIJ821 
after single s.c. injection 
● Incidence and severity of treatment-emergent 
adverse events (TEAEs), including AEs of 
special interest; standard safety assessments 
such as vital signs, ECG, hematology, blood 
chemistry, urinalysis; Clinician-Administered 
Dissociative States Scale (CADSS) score, 
Modified Observer's Assessment of 
Alertness/Sedation (MOAA/S), C-SSRS, 
memory assessment using orientation 
questions, results of local tolerability 
assessments 
● To assess MIJ821 PK in plasma after single 
s.c. injection 
● PK properties of MIJ821 in plasma described 
by Area under the curve from time zero to time 
of last measurable concentration (AUClast), 
maximum plasma drug concentration (Cmax), 
time to reach maximum plasma concentration 
(Tmax) (parameters not limited). 
● To assess the duration of antidepressant 
effect of MIJ821 
● MADRS total score at Day 8, 15, 22 and 29 
visits compared to baseline 
● To characterize the dose-response and 
exposure-response relationship of MIJ821 
● Dose-response relationship of MIJ821 with 
respect to change from baseline in MADRS total 
score at 24 hours after single s.c. injection 
● Exposure-response relationship of MIJ821 
with respect to change from baseline in MADRS 
total score at 24 hours (Day 2)  


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1.2.1 
Primary estimand(s) 
The primary clinical question of interest is: What is the effect of s.c. MIJ821 (versus placebo) 
given in addition to standard pharmacological antidepressant (SoC) treatment 24 hours after the 
injection of the study drug on change in depressive symptoms in participants with TRD, who 
have already failed to adequately respond to at least two conventional antidepressants.  
The justification for the primary estimand is that it will allow to estimate the rapid effect of the 
study drug in a population of depressed participants, who are considered treatment resistant, 
based on the definition above. A rapid response is clinically valuable as conventional 
antidepressants might need several weeks to achieve reduction of depressive symptoms. 
The primary estimand is described by the following attributes: 
1. Population: participants with treatment-resistant depression, who have failed to show 
adequate treatment response to at least 2 antidepressants previously. 
2. Primary variable/endpoint: change from baseline in MADRS total score at 24 hours post-
dose. 
3. Treatment of interest: the randomized treatment (the investigational treatment MIJ821 or 
the placebo treatment) administered as a single s.c. injection on Day 1. The dose of the 
allowed concomitant medication (i.e., SoC) for depression must remain stable during the 
trial. 
4. Handling of intercurrent events (IEs) prior to MADRS assessment at 24 hours: 
• New intake or change in concomitant medications/therapies which have a potential 
confounding effect: hypothetical strategy 
• Intake of prohibited medications: hypothetical strategy 
• Intake of rescue medications: hypothetical strategy 
• IEs related to pandemic: hypothetical strategy 
• IEs leading to study discontinuation due to adverse events (AEs), lack of efficacy or 
other reasons: treatment policy 




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the actual class of baseline antidepressants, which is based on the reported medications in the 
eCRF concomitant medication page, will be used in all the summary and analysis unless 
otherwise specified. 
2.1.1.2 
Study days and baseline derivation 
Day 1 
Day 1 or reference start date is defined as the day of dose administration (s.c. injection of the 
study drug). For participants who are randomized but not dosed, the Day 1 refers to the date of 
randomization. 
Study day 
The study day of a specific date of interest is calculated relative to Day 1 as follows: 
Before Day 1: Study day = (Date of interest – Date of Day 1). 
On or after Day 1: Study day = (Date of interest – Date of Day 1) + 1. 
Note that there is no Day 0, the day before Day 1 is referred as Day -1.  
Duration of an event is calculated as (event end date – event start date) + 1. 
Baseline 
Ideally the baseline values should be assessed at 1 hour before treatment on Day 1. In the 
analysis, a baseline value is defined as the last evaluable measurement prior to the study drug 
injection, irrespective of re-screening. In this case, baseline values will be the values obtained 
as the last valid pre-dose assessment on Day 1. If there is no valid assessment on Day 1, an 
earlier visit (scheduled or unscheduled) closest to the Day 1 visit will be picked and the last 
valid assessment on that day will be considered as baseline.  
The actual assessment time (if available) should be used when comparing multiple records on 
the same day. If actual time is not available, the planned time point should be used. If neither 
applies, the last valid record (i.e. the one with the largest record number) will be used. More 
programming details will be provided in the Programming Data Specification (PDS). 
Date of last contact 
For participants who die during the study, the death date will be used as the date of last contact. 
For other participants, the date of last contact will be derived as the last visit assessment date. 
Analysis cut-off date 
All available data will be used. Data after withdrawal of consent will be excluded from all TFL 
outputs. 
Treatment-emergent data 
The treatment-emergent data is defined as data collected after the study drug injection on Day 
1. Considering the short follow-up duration (29 days after baseline) of this study, all safety data 




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By-visit summary will be provided for the efficacy and safety endpoints 
 based on the 
scheduled visits. No prioritization of scheduled vs unscheduled visit will be made. In case of 
multiple assessment values among the same type of visit (i.e., scheduled vs. unscheduled) 
within the same analysis window, the closest to the scheduled visit day will be used. In case of 
equal distances (e.g., same day), the latest assessment value will be used.  
All results collected during study visits (scheduled or unscheduled) will be displayed in listings. 
2.2 
Analysis sets  
The Randomized set includes all randomized participants. 
The Full Analysis Set (FAS) comprises all randomized participants who received a dose of the 
randomized treatment. Participants will be analyzed according to the assigned treatment arms. 
The Safety Set (SAF) includes all participants who received any study drug. Participants will 
be analyzed according to the study treatment received. 
The PK analysis set will include all participants with at least one available valid (i.e. not 
flagged for exclusion) PK concentration measurement, who received any study drug and with 
no protocol deviations that impact on PK data. 
The number and percentage of patients in each analysis set will be summarized. 
The primary analysis and other analysis for other efficacy outcomes (including 
) will be 
performed on the FAS and the SAF will be used for all analysis of safety outcomes. 
Rule of exclusion criteria of analysis sets (For GenMeds use only): See Appendix 5-5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.3 
Other antidepressants or any combinations Patient disposition, 
demographics and other baseline characteristics 
2.3.1 
Patient disposition 
Participants’ disposition will be assessed at screening and at the end of study. 
The number of participants screened and rescreened will be reported. Subject dispositions at 
the end of screening phase will be summarized. The primary reason for not completing the 
screening phase will also be summarized. 
Information on inclusion and exclusion criteria will be provided for subset of screened patients 
not continuing to randomization. 
The number and percentage of participants who completed study will be summarized based on 
FAS. For early study discontinuations, the reasons will be summarized. 
The details of the screening and study dispositions will be listed at subject level. 
The number of patients randomized will be summarized by country. 
For protocol deviation (PD), the number and percentage of participants will be provided by PD 
category and deviation term and summarized for each arm. All PDs will be listed by treatment 
arms and by PD categories. 
2.3.2 
Demographics and other baseline characteristics 
Demographic variables and other baseline characteristics will be summarized for each 
randomized treatment arm and for all participants (total) based on Randomized set.  
Participant demographic and baseline characteristics will include: 
• Age 
• Sex  
• Ethnicity 
• Race 
• Height 
• Weight 
• BMI and BMI group (<25; >=25 and <30; >=30)  
• Employment status 
• Social status 
• Region (USA, Europe, Japan) 
Disease characteristics at baseline will include: 
• Drug class of baseline antidepressants: Selective Serotonin-Reuptake Inhibitors (SSRIs); 
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs); Other antidepressants or any 
combinations 


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• Baseline SoC category: Antidepressant in monotherapy; Antidepressants in combinations; 
Antidepressants + Augmentation 
• CYP2D6 metabolizer phenotypes classifications (Ultrarapid metabolizers, Normal 
metabolizers, Intermediate metabolizers, Poor metabolizers) 
• Baseline MADRS score and category (<30, 30-34, 35-40, >40) 
• Disease duration (years) derived as (randomized date – Date MDD first ever diagnosed) / 
365.25 
• Duration of current depressive episode (weeks) derived as (randomized date – onset date 
of current depressive episode) / 7 
• Total number of major depressive episodes in lifetime (excluding the current episode): 1, 
2, 3-5, >5 
• Overall severity of current episode (mild, moderate, severe, not reported) 
• Overall severity of the first episode (mild, moderate, severe, not reported) 
• Hospitalization events for current episode (Yes/No) 
• Does the participant have any biological relatives who have or had diagnosis of 
Psychiatric disorder (yes, no) 
• Current major depressive episode features 
• Anxious distress (yes/no) 
• Mixed features (yes/no) 
• Melancholic features (yes/no) 
• Atypical features (yes/no) 
• Catatonia (yes/no) 
• Seasonal pattern (yes/no) 
• Number of failed antidepressant treatments prior to screening in current MDE (<3, >= 3).  
• Reason for discontinuation of prior MDD related medication/therapies (due to lack of 
efficacy, adverse event, non-compliance, no longer required, others). 
The antidepressant category of patients at baseline is summarized based on the actual baseline 
ADs collected in eCRF CM page, in the case that patient has no baseline antidepressant reported, 
the randomization strata from the IRT system will be used.  
The baseline SoC category is summarized based on the number of ADs (monotherapy = only 
one AD; combinations = at least two ADs) and whether an augmentation therapy is used as 
combination therapy at baseline. The baseline SoC (AD or augmentation) is identified by 
CMCAT=” MDD RELATED MEDICATIONS” in CM data and the ADs are selected by 
ATC3=”ANTIDEPRESSANTS”. The augmentation therapies are reported with CMCAT=” 
MDD RELATED MEDICATIONS” in eCRF and confirmed during clinical review. 
Demographic and other baseline data will be summarized descriptively by treatment arm for all 
study participants in the Randomized set.  


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2.3.3 
Medical history and current medical condition 
Any medical history and current medical conditions at baseline for all randomized patients will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized 
by System Organ Class (SOC) and Preferred Term (PT) and by treatment arm. 
All previous major depressive episodes (including current MDE) will be collected for each 
patient. For the reported first and current MDEs, the following criteria will be used to impute 
the partial start dates, which will be used in calculation of the disease duration and the duration 
of current episode defined in Section 2.3.2. 
• If year and month are present and day is missing (YYYY-MM-XX), impute the start 
date as YYYY-MM-15; 
• If year is present and missing month and day (YYYY-XX-XX), use 01-July of that 
year (YYYY-07-01) as the start date. 
• If completely missing, no imputation will be performed. 
All collected information for MDEs will be listed at individual level and by treatment arms. No 
imputation is needed for the partial/missing start/end dates and the reported start/end dates will 
be used in the listing. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The study treatment is single injection of MIJ821 (10mg, 4mg or 1mg) or placebo on Day 1, 
the number of patients completed treatment will be reported by treatment arm based on SAF. 
Patients with protocol deviations related to treatment will be summarized in the PD summary 
table. 
In case of unblinding during the study, any efficacy-related PRO data (including MADRS, 
) collected after unblinding will be removed from the corresponding analysis. 
All safety data (including AE and safety-related PRO data) will be included in the 
corresponding analysis. 
2.4.2 
Prior, concomitant medications and non-drug therapies 
For the standardization of data display, all the prior and concomitant medications reported on 
eCRF page will be coded using the World Health Organization (WHO) drug dictionary, which 
employs the Anatomical Therapeutic Chemical classification (ATC) system. The version of the 
dictionary used will be reported in the TFL outputs. 
Non-drug therapies or procedures will be coded by Medical Dictionary for Regulatory 
Activities (MedDRA).  
All analysis for prior and concomitant medications will be performed based on the safety set 
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The prior medications/non-drug therapies are defined as drugs/non-drug therapies taken and 
stopped before the start of the study treatment on Day 1. Concomitant medications/non-drug 
therapies are defined as drugs taken at least once after the study treatment on Day 1.  
For missing start or stop dates of the reported medications, the dates will be imputed using 
Novartis standards (Section 5.1.3). 
Prior and Concomitant medications will be summarized separately based on ATC code (level 1 
and level 3), preferred term and treatment arm.  
Prior MDD-related medications will be summarized based on ATC code (level 1, 3 and 4), 
preferred term and treatment arm. 
Prior and Concomitant non-drug therapies will be summarized separately by primary system 
Organ Class and preferred term. 
2.4.2.1 
Current Standard of care (SoC) and psychotherapy use 
Current standard of care (SoC) is identified as (1) medications flagged as “MDD related 
medications” on the ‘prior or concomitant medication’ e-CRF page, (2) ongoing during 
treatment (i.e. started before first dose of study drug and ongoing thereafter) and (3) the 
medication is either an antidepressant (ATC3=”ANTIDEPRESSANTS”) or an augmentation 
drug as confirmed by clinical review.  
Psychotherapy is allowed to be used and needs to be stable during the study. Current allowed 
MDD related procedure (Psychotherapy) is identified as (1) flagged as “MDD related 
procedures” on the ‘prior or concomitant non-drug therapies/procedures’ e-CRF page, (2) is 
NOT listed in the prohibited medication table ([Table 6-2] in the protocol) and (3) ongoing 
during treatment (i.e. started before first dose of study drug and ongoing thereafter). 
Current standard of care (SoC) medications will be summarized by ATC code level 1, 3 and 4 
and preferred term and by treatment arms. Current allowed MDD related procedure will be 
listed by treatment arms. 
2.4.2.2 
Intercurrent events 
Medical review will be conducted to identify intercurrent events (IE) with onset happen post-
dose, especially before the 24 hours post-dose assessment of the primary outcome (MADRS 
score). A listing of any new/change in medication/therapies post the treatment will be generated 
for this purpose and the records happened within 24 hours post-dose will be marked. 
Intercurrent events may include:  
• New intake or change in baseline SoC medications/therapies which have a potential 
confounding effect. 
• Intake of prohibited medication/ therapy 
• Intake of rescue medications. 
 


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The rescue medications are identified by clinical judgement based on documented usage and 
indication of the drug. List of rescue medications (if any) identified by clinical team during 
medical review before DBL will be used in the CSR outputs. 
The listing of concomitant medications and therapies which qualify as intercurrent events with 
onset after injection on Day 1 will be provided and the records within 24 hours post-dose will 
be marked. The ‘24 hours post-dose’ will be based on the actual assessment date/time of the 
efficacy outcome on Day 2. Different flags will be used to mark different IEs. For SoC changed 
before 24 hours post-dose assessment, all records of the same drug will be listed and the first 
record of change will be flagged. For prohibited/rescue medications, any use during 24 hours 
post-dose will be flagged. 


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2.5 
Analysis supporting primary objective(s) 
The primary efficacy analysis will be conducted after all required data are collected and cleaned. 
The primary clinical question of interest is: What is the effect of s.c. MIJ821 versus placebo in 
addition to SoC at 24 hours after the injection of the study drugs on change in depressive 
symptoms measured by MADRS total score in participants with treatment resistant depression 
(TRD), who have already failed to adequately respond to at least two conventional 
antidepressants, while accounting for intercurrent events (IEs) with potential confounding 
effects and IEs leading to study discontinuation prior to 24 hours? 
2.5.1 
Primary estimand and endpoint(s) 
The primary estimand is described by the following attributes: 
1. Population: participants with treatment resistant depression, who have failed to show 
adequate treatment response to at least 2 antidepressants previously. 
2. Primary variable: change from baseline in MADRS total score at 24 hours post-dose 
3. Treatment of interest: the randomized treatment (the investigational treatment MIJ821 or 
the placebo treatment) administered as a single s.c. injection on Day 1. The dose of the 
allowed concomitant medication (SoC) for depression must remain stable after baseline 
and during the trial. 
4. Intercurrent Events (IEs) prior to MARDS assessment at 24 hours. 
IEs with potential confounding effect prior to the 24-hour assessment: 
• New intake or change in concomitant medications/therapies which have a potential 
confounding effect. 
• Intake of prohibited medications/therapies. 
• Intake of rescue medication. 
• Pandemic related IEs. 
• IEs leading to study discontinuation prior to the 24-hour assessment: 
• Adverse events (AE). 
• Lack of efficacy (LoE). 
• Other reasons for study discontinuation. 
5. The summary measure: treatment difference in variable means between study drug and 
placebo. 
The primary endpoint is the change from baseline in MADRS total score at 24 hours post 
study treatment.  
2.5.1.1 
Derivation of MADRS total score 
The MADRS consists of 10 items that cover all the core depressive symptoms (apparent sadness, 
reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, 
pessimistic thoughts, and suicidal thoughts). Each item is scored from 0 (item is not present or 
is normal) to 6 (severe or continuous presence of the symptom). For each item, a higher score 
represents a more severe condition. 




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The treatment-emergent period will be defined as starting from the date of administration of 
study treatment to EOS visit. Safety summaries (tables, figures) include only data from the on-
treatment period with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries). In particular, summary tables for adverse 
events (AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs). Treatment-Emergent Adverse Events (TEAEs) in this study 
are defined as adverse events starting or worsening after the administration of study medication 
and up to the EOS visit. That is, all the reported AEs collected post treatment will be considered 
as TEAEs, so we will simply use AEs all through this section to avoid any confusion. 
2.7.1 
Adverse events (AEs) 
The missing onset date of AE will be imputed using the Novartis standard imputation rules 
(Section 5.1.2). 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or later will be used 
to code Adverse Event (AE) to a SOC and a PT. The version used will be displayed in the table 
footnote.  
The number (and percentage) of participants with AEs will be summarized by following 
approach as defined in Table 2-6, in terms of all AEs, Serious Adverse Events (SAEs), 
treatment-related AEs or SAEs and fatal AEs that caused death: 
• by treatment arm, primary system organ class and preferred term 
• by treatment arm, primary system organ class, preferred term and maximum severity 
• by treatment arm, preferred term with most frequency (incidence rate > 10%) 
Table 2-6 
AE summaries 
Category 
by SOC and 
PT 
by SOC, PT 
and maximum 
severity 
by most 
frequent PT 
(≥ 10%) 
All AEs 
Y 
Y 
Y 
SAEs 
Y 
 
 
All treatment-related AEs 
Y 
Y 
 
Treatment-related SAEs 
Y 
 
 
For all AE tables presented by SOC and PT, the SOCs will be presented in alphabetical order 
and PTs will be ordered within the SOC by decreasing order of frequency. AE tables by 
preferred term only will be sorted in descending order of frequency. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. If a particular AE severity is missing, 
the variable will be listed as missing and treated as missing in summaries. If a participant 
reported more than one AE within the same SOC, the participant will be only counted once and 
the AE with greatest severity will be presented. Similar approach will be used to handle the 
situation of multiple AE within the same PT for the same participant. 


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The time to onset of AEs  will be summarized by PT by descriptive statistics.  
All AEs and SAEs will be listed separately at individual level and by treatment arms. 
Participants with any abnormal findings (worsening or newly occurring) in AE will be listed by 
treatment arms. This listing is used to evaluate the withdraw/rebound effect of MIJ821 after 2 
weeks of the treatment. A ‘newly occurring AE’ is defined as an AE that did not happen between 
treatment on Day 1 and the 2 weeks follow-up afterwards but happened after 2 weeks. A 
‘Worsening AE’ is defined as an AE happened between treatment and 2 weeks in follow-up, 
and the severity increased after 2 weeks. Note that the actual Day 15 visit time will be used for 
the 2-week cut-off time point. 
2.7.1.1 
Clinical trial safety disclosure 
For the legal requirements of ClinicalTrials.gov and European Union Drug Regulating 
Authorities Clinical Trials (EudraCT), following summaries listed in Table 2-7 will be provided. 
Table 2-7 
Safety disclosure requirements 
 
Requirements 
CT.GOV 
EudraCT 
SAE 
Number of subjects who had treatment emergent / on-treatment 
SAE 
Y 
Y 
Number of subjects who had on-treatment death 
Y 
Y 
Number of subjects who had on-treatment death due to SAE that 
were causally related to treatment 
 
Y 
Number of SAEs by SOC/PT 
Y 
Y 
Number of occurrences of SAEs by SOC/PT 
 
Y 
Number of occurrences of SAEs that were causally related to 
treatment by SOC/PT 
 
Y 
Number of SAEs, with outcome of death, related to treatment/all 
by SOC/PT 
 
Y 
NSAE 
Number of subjects who had treatment emergent / on-treatment 
Non-SAE with 0-5% threshold 
Y 
Y 
Number of Non-SAEs (0-5% threshold) by SOC/PT 
Y 
Y 
Number of occurrences of Non-SAEs with 0-5% threshold by 
SOC/PT 
 
Y 
2.7.1.2 
Adverse events of special interest / grouping of AEs 
The Adverse Events of Special Interest (AESI) is based on the availability of incremental 
clinical experience with MIJ821 and identified during safety review in electronic Compound 
Case Retrieval Strategy (CRS). MedDRA search criteria for AESIs will be identified by the 
latest version of CRS.  
AESI will be summarized by risk and by PT for each treatment arm for the on-treatment period. 
In addition, the investigator reported AESIs from the eCRF will be summarized similarly by 
risk and by PT and treatment arms. 


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The time to onset (starting from dosing on Day 1) and time to resolution (starting from first 
onset date) of each AESI will be summarized by descriptive statistics. Separate summary tables 
will be provided for AESIs started on dosing day (within 24 hours post-dose) and overall. In 
the case if a patient has multiple AESIs, the earliest starting time will be summarized for onset 
time and the latest end time will be used in summary of resolution time for that patient. The dot 
plot based on the onset time of each AESI at individual patient level will be provided for AESIs 
started on dosing day (within 24 hours post-dose) and overall. 
Listing of the above AESI will be provided at participant level and by treatment arms for both 
AESIs identified by CRS and investigator reported, separately. 
2.7.2 
Deaths 
Deaths (if any) will be summarized and listed under SAE by actual treatment arm. 
2.7.3 
Laboratory data 
Both of raw measures and change from baseline of laboratory results (hematology, blood 
chemistry) will be summarized by treatment arm and analysis visit.  
The clinical abnormality is defined as out of the normal ranges defined in the laboratory 
specification document. The newly occurring and worsening events are defined by comparing 
the measured laboratory parameters at baseline and post-baseline with the lower and/or upper 
limits of the normal ranges (see Table 2-8). In addition to the normal ranges, some of the lab 
parameters, which are covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0, will also be graded using the Novartis internal validated macro (with 
details covered in PDS) and the newly occurring and worsening events are also defined in Table 
2-8. The number and proportion of participants with newly occurring or worsening laboratory 
parameters based on normal ranges and CTCAE grades (if applicable) will be summarized by 
treatment arms and by visits (24 hours post-dose and EOS). 
Table 2-8 
Criteria for newly occurring or worsening laboratory parameters 
  
Event 
Baseline 
Post-baseline 
Under CTCAE grades 
Newly occurring 
Grade 0 (normal) 
Grade 1 - 4 (any abnormal) 
Missing 
Grade 1 - 4 (any abnormal) 
Worsening 
Grade 1 
Grade 2 - 4 
Grade 2 
Grade 3 - 4 
Grade 3 
Grade 4 
Under normal ranges 
Newly occurring 
Within normal range 
< LLN or > ULN 
Missing 
< LLN or > ULN 
< LLN 
> ULN 
> ULN 
< LLN 
Worsening 
BSL <  LLN 
VALUE < BSL < LLN  
BSL > ULN 
VALUE > BSL > ULN 
BSL = Baseline value; LLN = Lower limit of normal range; ULN = Upper limit of normal range. 


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Participants with any abnormal findings in laboratory values (newly occurring or worsening) 
will be listed by treatment arm. For parameters with CTCAE definitions, the CTCAE grades 
will be added in the listing and records with CTCAE grade of 3 or 4 will be flagged.  
To evaluate the potential drug-induced hepatotoxicity and renal signal, the liver and renal 
abnormalities at any time post-baseline will be analyzed by: 
• the number and proportion of participants with any newly occurring liver enzyme 
abnormalities based on each criterion defined in Table 5-1 in Appendix. 
• the number and proportion of participants with any renal abnormalities based on each 
criterion defined in Table 5-2 in Appendix. 
• listings of participants with clinically liver or renal abnormality. 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
2.7.4.1.1 Summary statistics of ECG parameter 
Summary statistics of ECG parameters (PR, QRS, QT, QTcF and RR intervals) recorded 
centrally will be presented by treatment and visit/time.  
2.7.4.1.2 Overall interpretation of the ECGs- ECG findings 
Recording of ECG finding (e.g., prolonged QTc, Torsade de Pointes, Ventricular Tachycardia, 
etc.) will be sent to Novartis by the central ECG vendor. 
ECG findings will be listed by treatment arm and visit/time. 
2.7.4.1.3 Clinically significant change in ECG parameters 
The incidence of abnormal ECG diagnosis (see Table 5-4 in appendix) will be presented in 
terms of count and percentage by treatment arm and by analysis visit.  
Participants with abnormal ECG values will be listed by treatment arms and by visit, and the 
worsening or newly occurring cases will be marked in the listing.  
Box plot for change from baseline of QTcF parameter will be provided by treatment arms and 
by visit. 
2.7.4.2 
Vital signs 
The analyses of vital signs (body temperature, systolic/diastolic blood pressure, pulse rate) and 
weight will include summary statistics for both the original measures (averaged means of three 
measures) and the change from baseline by treatment arm and by analysis visit. Boxplot and 
Mean+/-SD line plot of the change from baseline of blood pressure (SBP and DBP) over time 
will be provided by treatment arm. 
The number and percentage of participants with clinically relevant abnormality (see Table 5-3 
in appendix) at any post-baseline visit will be presented.  


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Participants with clinical relevant abnormality and any abnormal findings (worsening or newly 
occurring) will also be flagged in listings. 
2.7.4.3 
Clinician Administered Dissociative States Scale 
The Clinician Administered Dissociative States Scale (CADSS) is a questionnaire that assesses 
dissociative effects might related to MIJ821. The CADSS comprises 23 subjective items and 
participant’s responses are coded on a 5-point scale (0=” Not at all”, 1=” Mild”, 2=”Moderate”, 
3=”Severe” and 4=”Extreme”) based on their current experience. The CADSS will be assessed 
at baseline (Day 1, -1 hour pre-dose), 0.5 hour, 1.5 hour and 4-hour post-dose on Day 1, and 
follow-up assessments at Day 2 (24-hour), Day 8, Day 15, Day 22 and Day 29. 
The CADSS can be divided into 3 components using the following scoring method defined in 
Table 2-9. A higher score represents a more severe condition. Missing data at any subjective 
item will be unlikely since the items could not be skipped during the interview unless raters 
provide rationales, in which case the component scores and the total score will be calculated 
based on the proration approach. Specifically, if the percentage of missing items is more than 
10% of the total number of items for the component score, no imputation will be made and the 
component score will be missing. Otherwise, the sum of available items will be used and the 
component score is calculated as follows: 
Component score = Sum of scores from items present*(total number of items in the 
component/number of items present). 
 Table 2-9 
CADSS components and total scales 
Component 
Questions 
Range 
Depersonalization 
Sum of 3, 4, 5, 6, 7, 20, 23 
0-28 
Derealization 
Sum of 1, 2, 8, 9, 10, 11, 12, 13, 16, 17, 18, 19, 21 
0-52 
Amnesia 
Sum of 14, 15, 22 
0-12 
Total Score 
Sum of 1 through 23 
0-92 
For the total score and each component score (depersonalization, derealization and amnesia), 
the summary table of original measures and change from baseline values will be provided by 
treatment arm and analysis visit. The component scores for patients with CADSS total score >0 
at any post-dose visit will be listed. Boxplots will also be provided for change from baseline 
values for the total score over time by treatment arms.  
In addition, the number and percentage of participants satisfying the following criteria will be 
summarized separately by treatment arms and by analysis visit. 
• CADSS total score > 4 and change from baseline > 0. 
• Change from baseline in CADSS total score > 4.  
2.7.4.4 
Modified Observer's Assessment of Alertness/Sedation 
The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) will be used to assess 
participant responsiveness and measure sedation associated with MIJ821. The MOAA/S scores 


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range from 0 [No response to painful stimulus] to 5 [Readily responds to name spoken in normal 
tone (awake)]. A lower score of MOAA/S indicates more severe condition of sedation. 
The MOAA/S will be taken at the same visits and time points as CADSS. The following 
summary table and/or plots will be provided: 
• A stacked bar plot for categorical MOAA/S score by treatment arm and analysis visit.  
• Summary table and bar-plot comparing the percentage of participants with any sedation 
(MOAA/S<=4) across treatment arms over time. 
• Summary table and bar-plot comparing the percentage of participants with severe sedation 
(MOAA/S<=2) across treatment arms over time. 
2.7.4.5 
Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and behavior (SIB) and non-suicidal self-injurious, as well as 
intensity assessments for suicidal ideation, as summarized in Table 2-10 below. The 11 
preferred SIB categories include five levels of suicidal ideation, five levels of suicidal 
behavior and the category non-suicidal self-injurious. Each category has a binary response 
(yes/no). For this study, participants who have suicidal ideation with intent (answered ‘Yes’ 
for question 4 or 5) at baseline will be excluded from the study as screening failure.  
The C-SSRS will be assessed at Screening, Baseline (Day 1, -1 hour pre-dose), 4-hour post-
dose on Day 1, and follow-up visits at 24 hour (Day 2), Day 8, Day 15, Day 22 and Day 29 
(EOS). The SIB assessments obtained during screening will be based on participant’s 
experience during lifetime and past 1 month. All follow-up visits will be based on participant’s 
experience since last visit.  
The analysis for this scale will be based on the SAF. No safety cut-off will be applied for the 
SIB data reporting, i.e., all collected data will be used in the analysis. 
Patients who answered “yes” to each question in Table 2-10 will be counted by treatment arm 
and by visit. The descriptive statistics will be provided for the suicidal ideation score (the most 
severe suicidal ideation) by treatment arm and by visit.  
Suicidal ideation and behavior data will be listed. Detailed answers to C-SSRS items will be 
listed separately for subjects with any suicidal ideation at any time post-baseline (i.e., a ‘yes’ 
answer to at least one of the five suicidal ideation questions at any time post-baseline) and for 
a subject with any suicidal behavior at any time post-baseline (i.e., a ‘yes’ answer to at least one 
of the five suicidal behavior questions at any time post-baseline). 
Table 2-10 
C-SSRS components 
Category 
number 
C-SSRS category 
Suicidal Ideation 
1 
Wish to be dead 
2 
Non-specific active suicidal thoughts 
3 
Active suicidal ideation with any methods (not plan) without intent to act 
4 
Active suicidal ideation with some intent to act, without specific plan 


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Category 
number 
C-SSRS category 
5 
Active suicidal ideation with specific plan and intent 
Suicidal behavior 
6 
Preparatory acts or behavior 
7 
Aborted attempt 
8 
Interrupted attempt 
9 
Actual attempt 
10 
Completed suicide 
Self-injurious behavior, without suicidal intent 
11 
Non-suicidal self-injurious behavior 
2.7.4.6 
Amnesia/ memory gaps 
For participants who have amnesia reported as AE after completing the memory assessment 
questions, the memory gap eCRF page will be filled. 
A listing will be provided for participants with memory gaps by treatment arms. 
2.8 
Pharmacokinetic endpoints 
2.8.1 
Variables 
Pharmacokinetic (PK) plasma samples will be collected from each study participant in 
accordance with the assessment schedule to determine the MIJ821 concentration. Only samples 
from participants treated with MIJ821 will be analyzed. Concentrations will be expressed in 
mass per volume units. 
The following PK parameters will be determined after single s.c. injection using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
8.0 or higher): 
• primary PK parameters: AUClast, Tmax, and Cmax 
• secondary PK parameters: if data permit, additional PK parameters will be estimated e.g. 
T1/2, AUCinf, AUC0-t (if needed, time range to be defined during PK analysis), CL/F, 
Vz/F (data not limited) 
2.8.2 
Descriptive analyses 
In addition to the commonly used statistics, additional statistics will be used for summarizing 
the PK endpoints. The N values are defined as the number of participants with valid measures 
in each dose arms in the PK analysis set. The %CV (coefficient of variation percent) values will 
be summarized using the arithmetic mean calculated as ‘100*(standard deviation / mean)’ and 
the geometric mean calculated as ‘sqrt (exp (variance for log transformed data)-1)*100’. 
All MIJ821 plasma concentrations and PK parameters including their descriptive statistics will 
be presented with three significant figures. The exception will be %CV values, which will be 
reported to one decimal place and N values, which will be reported as whole integers. 






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2.9 
PD and PK/PD analyses 
The exposure response relationship will be presented graphically for PK exposure parameters 
(e.g. Cmax and AUClast) and the change from baseline MADRS score derived at 24 h postdose 
and Day 8, Day 15, Day 22 and Day 29 during the follow-up.  
Correlations will be assessed using statistical analysis methods (e.g. trendline analysis methods) 
and simple exposure response models (e.g. Sigmoid Emax models). Scatter plots of change 
from baseline of MADRS score (y-axis) versus PK exposure parameter (x-axis) will be 
provided by visit and the fitted lines and 90% pointwise confidence intervals from both the 
trendline analysis and Sigmoid Emax model will be added in the plots separately for each visit. 
The hill parameter in the Sigmoid Emax models will be estimated if data allows. In case the 
model dose not converge, the Emax model with hill parameter equals 1 will be used. A table 
with estimated placebo effect and estimated parameters from the Sigmoid Emax models will be 
presented by visit. 
 
 
 
 


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5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Not applicable. 
5.1.2 
AE date imputation 
Missing or partial start/stop dates for AE will be listed as it is in the associated listings. 
For analysis that needs to use the start date of an AE, e.g. in determination of whether an AE is 
treatment-emergent, the details will be provided in the programming dataset specification 
(PDS). 
5.1.3 
Concomitant medication date imputation 
Missing or partial start/stop dates and time for concomitant medication will be listed as it is in 
the associated listings. 
For analysis that needs the start date and time of concomitant medication, the details of 
date/time imputation will be provided in the programming dataset specification (PDS). 
5.1.3.1 
Prior therapies date imputation 
For prior medications with a stop date prior to Day 1, the start date will be imputed as the 
earliest possible start date and the stop date as the latest possible stop date. More details will be 
covered in the PDS. 
5.1.4 
Baseline SoC categories 
The summary of baseline standard of care is based on the categories of antidepressants (ADs) 
and augmentation therapies. Since some of the drugs of interest (e.g., SNRIs) cannot be 
identified based on the available ATC codes, and some augmentation therapies rely on the 
clinical review. A list of the drug class of interest (SSRI, SNRI, Other AD and Augmentation 
therapy) will be provided as a result of the clinical review on our blinded CM data and used for 
programming of the outputs. More details will be provided in the PDS.  
5.2 
AEs coding/grading 
The reported terms of adverse events will be coded by primary system organ class and preferred 
term using Medical Dictionary for Regulatory Activities (MedDRA) with version 25.0 or above. 
5.3 
Laboratory parameters derivations 
The grading for most of the lab parameters collected in hematology, chemistry, urinalysis and 
coagulation are defined using the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. The grading criteria for these parameters are adapted in a validated Novartis macro 


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and will be applied to the lab parameters to derive the CTCAE grades. Note that the macro is 
based on a simplified version of the CTCAE criteria considering programming feasibilities, e.g.: 
• For certain laboratory parameters the CTCAE grade definition was simplified in the macro 
to rely on laboratory results only (i.e., information from adverse events and/or other 
clinical assessment are not considered in the definition of CTCAE terms). 
• For laboratory parameters that depend on baseline values, the Novartis macro simplified 
the rule to have the grade only defined on normal range limits (LLN or ULN) value 
without considering the baseline values. This is a conservative approach and allows 
grading of post-baseline values even if baseline values are missing. 
More details of the CTCAE macro will be provided in the PDS. 
Liver abnormality are defined using the criteria listed in Table 5-1. The following are covered: 
hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; non-infectious 
hepatitis; benign, malignant and unspecified liver neoplasms upper limit of normal. 
Table 5-1 
Liver abnormality criteria 
 
Definition/ threshold 
For each assessment: 
ALT > 3x ULN                                    
ALT > 5x ULN                                    
ALT > 8x ULN                                    
ALT > 10x ULN                                   
ALT > 20x ULN                                   
ALT or AST > 3x ULN                             
ALT or AST > 5x ULN                             
ALT or AST > 8x ULN                             
ALT or AST > 10x ULN                            
ALT or AST > 20x ULN                            
ALT or AST > 3x ULN & TBL > 1.5x ULN            
ALT or AST > 3x ULN & TBL > 2x ULN              
ALP > 1.5x ULN                                  
ALP > 2x ULN                                    
ALP > 3x ULN                                    
ALP > 5x ULN                                    
TBL > 1x ULN                                    
TBL > 1.5x ULN                                  
TBL > 2x ULN                                    
TBL > 3x ULN                                    
ALP > 3x ULN & TBL > 2x ULN                     
ALP > 5x ULN & TBL > 2x ULN  
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
Total bilirubin > 2 × ULN and ALP ≤ 2 × ULN) 
Any clinical event of jaundice (or equivalent term)                    
If ALT or AST abnormal at 
baseline: 
ALT or AST > 2x baseline or > 200 U/L (whichever occurs first) 










Novartis 
Confidential 
Page 47 of 47 
SAP 
 
Study No. MIJ821B12201 
 
 
5.5 
Rule of exclusion criteria of analysis sets  
Table 5-5 
Participants classification 
Analysis Set 
Criteria that cause  
subjects to be excluded 
FAS 
Not randomized 
Mistakenly randomized and no double-blind study drug taken 
SAF 
No double-blind study drug taken 
6 
Reference 
Bretz F, Pinheiro JC, Branson M (2005) Combining multiple comparisons and modeling 
techniques in dose-response studies. Biometrics: 738-48. 
Rubin, D. B. (1976). Inference and missing data. Biometrika, 63(3), 581-592. 
Rubin, D. B. (2004). Multiple imputation for nonresponse in surveys (Vol. 81). John Wiley & 
Sons.