A Multi-center, Randomized, subject-and Investigator Blinded, Placebo-controlled, Active Comparator, Parallel-group Proof of Concept Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of MIJ821 in Patients With Treatment-resistant Depression
Phase: PHASE2
Conditions: Depressive Disorder, Treatment-Resistant
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
MIJ821
Clinical Trial Protocol CMIJ821X2201
A multi-center, randomized, subject and investigator-
blinded, placebo-controlled, active comparator, parallel-
group proof of concept study to evaluate the efficacy, 
safety, tolerability, and pharmacokinetics of MIJ821 in 
patients with treatment-resistant depression
Document type:
Amended Protocol Version
EUDRACT number:
2018-003002-12
Version number:
02 (Clean)
Clinical Trial Phase:
II
Release date:
10-Jul-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................18
2
Objectives and endpoints...................................................................................................19
3
Study design ......................................................................................................................20
4
Rationale............................................................................................................................22
4.1
Rationale for study design .....................................................................................22
4.2
Rationale for dose/regimen and duration of treatment ..........................................22
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................23
4.4
Purpose and timing of interim analyses/design adaptations..................................24
4.5
Risks and benefits..................................................................................................24
4.5.1
Blood sample volume............................................................................26
5
Population..........................................................................................................................27
5.1
Inclusion criteria ....................................................................................................27
5.2
Exclusion criteria...................................................................................................28
6
Treatment...........................................................................................................................30
6.1
Study treatment......................................................................................................30
6.1.1
Investigational and control drugs..........................................................30
6.1.2
Additional study treatments ..................................................................30
6.1.3
Treatment arms/group ...........................................................................30
6.2
Other treatment(s)..................................................................................................31
6.2.1
Concomitant therapy.............................................................................31
6.2.2
Prohibited medication ...........................................................................31
6.2.3
Restriction for study subjects................................................................32
6.3
Subject numbering, treatment assignment, randomization....................................32
6.3.1
Subject numbering ................................................................................32
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6.3.2
Treatment assignment, randomization ..................................................32
6.4
Treatment blinding.................................................................................................32
6.5
Dose escalation and dose modification..................................................................34
6.6
Additional treatment guidance...............................................................................35
6.6.1
Treatment compliance...........................................................................35
6.6.2
Recommended treatment of adverse events..........................................35
6.6.3
Emergency breaking of assigned treatment code..................................35
6.7
Preparation and dispensation.................................................................................36
7
Informed consent procedures ............................................................................................36
8
Visit schedule and assessments .........................................................................................37
8.1
Screening ...............................................................................................................43
8.1.1
Information to be collected on screening failures.................................43
8.2
Subject demographics/other baseline characteristics.............................................43
8.3
Efficacy..................................................................................................................43
8.3.1
Montgomery Asberg Depression Rating Scale.....................................43
8.3.4
Appropriateness of efficacy assessments..............................................45
8.4
Safety / Tolerability...............................................................................................45
8.4.1
Laboratory evaluations..........................................................................46
8.4.2
Electrocardiogram (ECG) .....................................................................47
8.4.3
Pregnancy and assessments of fertility .................................................47
8.5
Additional assessments..........................................................................................48
8.5.1
Clinical Outcome Assessments (COAs) ...............................................48
8.5.2
Pharmacokinetics ..................................................................................51
9
Study discontinuation and completion ..............................................................................53
9.1
Discontinuation......................................................................................................53
9.1.1
Discontinuation of study treatment .......................................................53
9.1.2
Withdrawal of informed consent...........................................................54
9.1.3
Lost to follow-up...................................................................................54
9.1.4
Study stopping rules..............................................................................55
9.1.5
Early study termination by the sponsor.................................................55
9.2
Study completion and post-study treatment ..........................................................55
10 Safety monitoring and reporting........................................................................................56
10.1
Definition of adverse events and reporting requirements......................................56
10.1.1
Adverse events ......................................................................................56
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10.1.2
Serious adverse events ..........................................................................57
10.1.3
SAE reporting........................................................................................58
10.1.4
Pregnancy reporting ..............................................................................59
10.1.5
Reporting of study treatment errors including misuse/abuse................60
10.2
Additional Safety Monitoring................................................................................60
10.2.1
Liver safety monitoring.........................................................................60
10.2.2
Renal safety monitoring........................................................................61
10.2.3
Prospective suicidality assessment........................................................61
10.2.4
Data Monitoring Committee .................................................................62
11 Data Collection and Database management......................................................................62
11.1
Data collection.......................................................................................................62
11.2
Database management and quality control............................................................62
11.3
Site monitoring ......................................................................................................63
12 Data analysis and statistical methods ................................................................................64
12.1
Analysis sets ..........................................................................................................64
12.2
Subject demographics and other baseline characteristics......................................64
12.3
Treatments .............................................................................................................64
12.4
Analysis of the primary endpoint(s) ......................................................................64
12.4.1
Definition of primary endpoint(s).........................................................65
12.4.2
Statistical model, hypothesis, and method of analysis..........................65
12.4.3
Handling of missing values/censoring/discontinuations.......................65
12.4.4
Sensitivity and Supportive analyses......................................................65
12.5
Analysis of secondary endpoints ...........................................................................66
12.5.1
Efficacy and/or Pharmacodynamics endpoint(s) ..................................66
12.5.2
Safety endpoints....................................................................................67
12.5.3
Pharmacokinetics ..................................................................................68
12.5.4
PK/PD relationships..............................................................................69
12.5.5
Patient reported outcomes.....................................................................69
12.6
Analysis of exploratory endpoints.........................................................................69
12.6.3
Other Exploratory Endpoints ................................................................69
12.7
Interim analyses.....................................................................................................69
12.8
Sample size calculation..........................................................................................70
12.8.1
Primary endpoint(s)...............................................................................70
12.8.2
Secondary endpoint(s)...........................................................................70
13 Ethical considerations and administrative procedures ......................................................71
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13.1
Regulatory and ethical compliance........................................................................71
13.2
Responsibilities of the investigator and IRB/IEC..................................................71
13.3
Publication of study protocol and results...............................................................71
13.4
Quality Control and Quality Assurance.................................................................71
14 Protocol adherence ............................................................................................................72
14.1
Protocol Amendments ...........................................................................................72
15 References .........................................................................................................................73
16 Appendices ........................................................................................................................75
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................75
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up......78
List of tables
Table 2-1
Objectives and related endpoints ..........................................................19
Table 6-1
Overview of study medication ..............................................................30
Table 6-2
Blinding and unblinding plan................................................................34
Table 8-1
Assessment Schedule ............................................................................38
Table 8-2
Laboratory Assessments........................................................................46
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................60
Table 16-1
Liver Event and Laboratory Trigger Definitions ..................................75
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers...76
Table 16-3
Specific Renal Alert Criteria and Actions.............................................78
Table 16-4
Renal Event Follow Up.........................................................................79
List of figures
Figure 3-1
Study design..........................................................................................21
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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APA
American Psychological Association
AR(1)
first-order autoregressive
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
BP
Blood Pressure
BRMS
Bech-Rafaelsen Melancholia Scale
BUN
blood urea nitrogen
C-SSRS
Columbia Suicide Severity Rating Scale
CADSS
Clinical-Administered Dissociative States Scale
CFR
U.S. Code of Federal Regulations
CGI
Clinical Global Impression
CGI-I
Clinical Global Impression of Improvement
CGI-S
Clinical Global Impression of Severity
CK
creatinine kinase
CL
apparent total body clearance of the drug from plasma
cm
centimeter(s)
Cmax
maximum plasma drug concentration
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central Nervous System
CO2
carbon dioxide
CRA
Compliance and Regulatory Affairs
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTC
Common Toxicity Criteria
CV
coefficient of variation
DAE
Dissociative adverse event
DAR
Dose Administration Record
DDE
Direct Data Entry
DES
Dissociative Experiences Scale
DNA
Deoxyribonucleic Acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
Electrocardiogram
eCRF
electronic Case Report Form
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EDC
Electronic Data Capture
EMA
European Medicines Agency
EU
Europe
FAS
Full Analysis Set
FIH
First in Human
FSH
Follicle Stimulating Hormone
GASE
Generic Assessment of Side Effects
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
GLP
Good Laboratory Practice
h
Hour
HAM-A
Hamilton Anxiety Rating Scale
HIV
human immunodeficiency virus
hsCRP
High Sensitivity C-Reactive Protein
IB
Investigator's Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IL
Interleukin
IN
Investigator Notification
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
Intent-to-Treat
IUD
intrauterine device
IUS
intrauterine system
kg
killogram(s)
KMDRS
Koukopoulos Mixed Depression Rating Scale
KR
Kenward-Roger
LC-MS/MS
Liquid Chromatography-tandem Mass Spectrometry
LDH
lactate dehydrogenase
MADRS
Montgomery Asberg Depression Rating Scale
MDD
Major Depressive Disorder
MDE
Major Depressive Episode
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMDC
Melancholia and Mixed Depression Diagnostic Checklist
MMRM
Mixed-effects Model for Repeated Measures
MTI
Maudsley Treatment Inventory
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NIRT
Novartis Interactive Response Technology
NMDA
N-methyl-D-aspartate
NOEL
No Observable Effect Level
PD
pharmacodynamic(s)
PHQ
Patient Health Questionnaire
PK
pharmacokinetic(s)
PPS
per protocol set
QMS
Quality Management System
QTcB
QT interval corrected by Bazett's formula
QTcF
QT interval corrected by Fridericia’s formula
RBC
red blood cell(s)
RoW
Rest of World
SAE
serious adverse event
SCID-5(-RV)
Structured Clinical Interview for DSM-5 (Research Version)
SD
standard deviation
SMPI
Sydney Melancholia Prototype Index
SMQ
Standardized MedDRA Query
SOM
Site Operations Manual
STS
Suicidality Tracking Scale
SUSAR
Suspected Unexpected Serious Adverse Reactions
T1/2
Elimination half-life
Tmax
time to reach maximum plasma concentration
TRD
Treatment-Resistant Depression
TSH
thyroid-stimulating hormone
ULQ
Upper Limit of Quantification
UN
unstructured
US
United States
Vz
apparent volume of distribution during terminal phase
WBC
white blood cell(s)
WHO
World Health Organization
WOC
Withdrawal of consent
β-hCG
Beta-Human Chorionic Gonadotropin

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject 
Cohort
A specific group of subjects fulfilling certain criteria
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
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 
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 paper source forms 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 subject or 
at a later point in time as defined by the protocol
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up) which 
applies across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource 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.
Healthy volunteer
A person with no known significant health problems who volunteers to be 
a study participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a 
single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest for the study
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples
Randomization 
number
A unique identifier assigned to each randomized subject
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource

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Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of consent 
(WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data

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Protocol No. CMIJ821X2201
Protocol summary
Protocol number
CMIJ821X2201
Full Title
A multi-center, randomized, subject
and investigator-blinded, placebo-
controlled, active comparator, parallel-group proof of concept study to evaluate 
the efficacy, safety, tolerability, and pharmacokinetics of MIJ821 in patients 
with treatment-resistant depression
Brief title
Study of efficacy and safety of MIJ821 in treatment-resistant depression 
patients.
Sponsor and 
Clinical Phase
Novartis
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The main purpose of this non-confirmatory study is to evaluate the clinical 
responses of MIJ821 in patients suffering from treatment-resistant depression 
assessed 
by 
the 
Montgomery 
Åsberg
Depression 
Rating 
Scale 
(Montgomery and Asberg 1979).
Furthermore it is expected that this study will guide the future clinical trials with 
MIJ821 in treatment of resistant depression.
Primary 
Objective(s)
The primary objective of this study is to assess the efficacy of MIJ821 in 
treatment-resistant depression at 24 hours after the start of infusion. 
The measure will be conducted through MADRS total score, 24 hours after the 
start of first infusion compared to the baseline assessment.
Secondary 
Objectives
To assess the efficacy of MIJ821 in treatment-resistant depression by 1) 
evaluating the percentage of treatment response (>50% improvement in 
MADRS) at 24 hours, 48 hours (if applicable) and 6 weeks after the start of first 
infusion 2) evaluating the percentage of remission (MADRS <7) at 24 hours, 
48 hours (if applicable) and 6 weeks after the start of first infusion; 3) evaluating 
the CGI-I and CGI-S scores at 24 hours, 48 hours (if applicable), and 6 weeks
after the start of first infusion.
To assess the impact of MIJ821 on suicidality.
To assess the MIJ821 pharmacokinetics in plasma.
To assess the most effective dose and dosing regimen.
To assess the safety and tolerability of weekly and bi-weekly infusions of 
MIJ821.
To assess the efficacy in melancholic subtype of depression.
To assess the risk of mania induction.
To assess the efficacy of MIJ821 for mixed mood symptoms.
To assess the efficacy of MIJ821 for anxiety symptoms.
To assess the impact of mixed mood symptoms, melancholia, and anxiety as 
predictors of treatment response to MIJ821.

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Study design
This is a multi-center, randomized, parallel group, active comparator, placebo-
controlled study. The study will enroll approximately 66 subjects presenting 
with Treatment-Resistant Depression. The study consists of a screening and 
baseline period (D-28 to D-1), a treatment period (D1 to D36) and a 5 week 
follow-up period with an end of study visit on Day 71. The maximum duration 
of the study including screening is approximately 14 weeks.
Population
Male and female subjects, 18 to 65 years (inclusive), diagnosed with 
Treatment-Resistant Depression. Eligible subjects may come from either an 
inpatient or outpatient treatment setting.
Key Inclusion 
criteria

Signed informed consent must be obtained prior to participation in the
study.

Male and female subjects, 18 to 65 years of age (inclusive) at screening.

Subject is in a DSM-5 defined major depressive episode at the time of
screening

Subject obtains a Montgomery-Åsberg Depression Rating Scale
(MADRS) score ≥ 24 at screening and baseline

Failure to response to two or more prior antidepressant treatments,
where two failed treatments are of two different antidepressants, with
adequate dose and duration (≥ 8 weeks duration, doses defined per
agent) for the current or prior major depressive episode, as identified by
the Maudsley Treatment Inventory, and prior psychiatric history,
assessed by the investigator, and further documented by medical records
and/or third party report (family, friends, clinician-treaters) where
available

At least one prior clinical depressive episode (recurrent major depressive
disorder), as identified by prior psychiatric history assessed by the
investigator, and further documented by medical records and third party
report (family, friends, clinician-treaters) where available.
Key Exclusion 
criteria

Any current diagnosis of bipolar disorder, schizophrenia, or
schizoaffective disorder.

Current alcohol or substance use disorder (including marijuana and
prescribed amphetamine) meeting DSM-5 criteria, within the past month
at baseline. Nicotine and caffeine use disorders are not considered as
exclusionary substances.

Prior suicidality caused by or associated with ketamine, as identified by
prior psychiatric history assessed by the investigator, and augmented by
medical records and third party report (family, friends, clinician-treaters)
where available.

Acute serious and/or imminent suicidal ideation and/or intent within the
prior 2 weeks, or any suicide attempt within the prior 4 weeks at
screening. Mild to moderate suicidal ideation, using the Sheehan Suicidal
Ideation Scale and not meeting the above definition, is not an exclusion
criterion.

Use of other investigational drugs within 30 days or 5 half-lives of
randomization, whichever was longer; or longer if required by local
regulations.

Current pregnancy or lactation.

Positive HIV, Hepatitis B or C test.

Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment
baseline.

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Study treatment
Patients who meet the eligibility criteria at screening and baseline will be 
randomized to one of the six treatment arms in the European countries (only 
five arms in the USA as there is no ketamine arm)
Efficacy 
assessments

Montgomery Åsberg Depression Rating Scale at 24 hours post-dose

% treatment response (>50% improvement in MADRS) at 24 hours, 48
hours (if applicable), and 6 weeks after the start of first infusion

% treatment remission (MADRS<7) at 24 hours, 48 hours (if applicable),
and 6 weeks after the start of first infusion

CGI-S and CGI-I scores at 24 hours, 48 hours (if applicable), and 6
weeks after the start of first infusion Sheehan Suicidality Tracking Scale
score changes from baseline at 24 hours, 48 hours (if applicable), and 6
weeks after the start of first infusion

Montgomery Åsberg Depression Rating Scale score at 6 weeks after the
start of first infusion
Other 
assessments
Pharmacokinetic 
assessments
MIJ821 pharmacokinetics in plasma
Key safety 
assessments
Adverse event monitoring, Physical examinations, Monitoring of laboratory 
markers in blood and urine, ECGs.
Data analysis
The change from baseline in the total MADRS score at 24 hours after single 
dose administration will be analyzed using an analysis of covariance 
(ANCOVA) model with treatment as a group factor and baseline MADRS score 
as a covariate. 
Key words
Treatment-Resistant Depression; Major Depressive Episode; Major 
Depressive Disorder
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1
Introduction
1.1
Background
Treatment-resistant depression (TRD) is defined as a failure to respond to at least two different 
antidepressants for a period longer than 4-6 weeks at the maximum recommended dose 
(Sackeim 2001). One-third or more of patients suffering from unipolar depressive illness, 
defined in DSM-5 as major depressive disorder (MDD), fail to respond acutely to antidepressant 
treatment of adequate dose and duration (Rush et al 2006). Even more subjects, the majority in 
fact, fail to maintain long-term response to standard antidepressants (Rush et al 2006).  
Further, suicide is a major harm with depressive illness, with depression being present in the 
vast majority of persons who commit suicide (Isometsä 2001). Most antidepressants have a few 
weeks delay in symptom benefit, during which time individuals can be at suicidal risk.
Ketamine, which is a 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 
NMDA receptor inhibition as a rapid-onset antidepressant mechanism. 
1.2
Purpose
The main purpose of this non-confirmatory study is to evaluate the clinical responses of MIJ821 
in subjects suffering from treatment-resistant depression assessed by the Montgomery Åsberg 
Depression Rating Scale (Montgomery and Asberg 1979), a validated and widely employed 
method in depression trials.
Furthermore, it is expected that this study will guide the future clinical trials with MIJ821 in 
patients with treatment resistant depression.
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2
Objectives and endpoints
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 in treatment-
resistant depression.

Montgomery Asberg Depression Rating Scale
total score at 24 hours after the start of the
infusion compared to the baseline
assessment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess risk of mania induction.

Young Mania Rating Scale at 24 hours, 48
hours (if applicable) and 6 weeks post-dose.

To assess efficacy in the melancholic
subtype of depression.

Bech-Rafaelsen Melancholia and CORE scale
change from baseline to 24 hours, 48 hours (if
applicable) and 6 weeks post-dose.

To assess safety and tolerability,
especially dissociative side effects.

Incidence of adverse event
Dissociative rating scales (Clinician-
Administered Dissociative States Scale, and
Dissociative Experiences Scale) change from
baseline to 24 hours, 48 hours (if applicable)
and 6 weeks post-dose.

To assess most effective dose and dosing
regimen.

Montgomery Åsberg Depression Rating Scale
score at 6 weeks.

To assess MIJ821 pharmacokinetics in
plasma.

PK properties of MIJ821 in plasma described
by AUClast, AUC0-24h, Cmax, Tmax
(parameters not limited)

To assess impact of MIJ821 on suicidality.

Sheehan Suicidality Tracking Scale changes
from baseline at 24 hours, 48 hours (if 
applicable), and 6 weeks after the start of first 
infusion.

To assess efficacy of MIJ821 on measures
of response and remission

% treatment response (>50% improvement in
MADRS) at 24 hours, 48 hours (if applicable),
and 6 weeks after the start of first infusion.
% treatment remission (MADRS<7) at 24
hours, 48 hours (if applicable), and 6 weeks
after the start of first infusion
CGI-S and CGI-I scores at 24 hours, 48 hours
(if applicable), and 6 weeks after the start of
first infusion

To assess efficacy of MIJ821 for mixed
mood symptoms.

Koukopoulos Mixed Depression Rating Scale
change from baseline to 24 hours, 48 hours,
and 6 weeks after the start of first infusion.

To assess efficacy of MIJ821 for anxiety
symptoms.

Hamilton Anxiety Scale change from baseline
to 24 hours, 48 hours (if applicable), and 6
weeks after the start of first infusion

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Objective(s)
Endpoint(s)

To assess impact of mixed mood
symptoms, melancholia, and anxiety as
predictors of treatment response to
MIJ821.

Regression model effect sizes (odds ratios) for
Hamilton Anxiety Scale, Bech-Rafaelsen
Melancholia Scale, and Koukopoulos Mixed
Depression Rating Scale as predictors, with
MADRS treatment response as outcome, at
24 hours, 48 hours (if applicable), and 6
weeks after the start of first infusion.
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
3
Study design
This is a non-confirmatory, multi-center, 6-treatment arm in the European countries and 
5-treatment arm in the USA (no ketamine arm), randomized, subject and investigator blinded,
parallel group, placebo controlled study in treatment-resistant depression patients. The study
will randomize approximately 66 Subjects and while the study design utilizes an outpatient visit
schedule, the study allows for the inclusion of subjects seeking treatment for their disease from
both an 'inpatient' or 'outpatient' clinic setting.
A screening period of maximum 4 weeks will be used to assess eligibility. Patients who meet 
the eligibility criteria at screening will proceed to baseline evaluations on Day-1 or Day 1. 
All baseline safety evaluation results must be available prior to randomization. At the baseline 
visit, eligible subjects will be randomized to one of the treatment arms. Randomized subjects 
will enter a 36- day treatment period, receiving at each treatment visit, a 40-minute infusion 
with a safety observation period of 2-4 hours (i.e. a minimum of 2 hours) post the start of 
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infusion. If the subject reports no dissociative symptoms and no suicidal symptoms, the subject 
will be allowed to leave the clinical treatment setting. Visits to assess efficacy and safety are 
scheduled at 24 hours, 48 hours (if applicable) and every week during the treatment period. 
If 48 hour visit (V103) is conducted, then all assessments should be completed. The assessment 
to address the primary objective will be performed at 24 hour post-dose. Safety assessments 
will include physical examinations, ECGs, vital signs, standard clinical laboratory evaluations 
(hematology, blood chemistry, and urinalysis), adverse event and serious adverse event 
monitoring. At the conclusion of the treatment period (Day 1 - Day 36), subjects will enter a 
5-week follow up period consisting of two follow visits approximately 1 week (Day 43) and
3 weeks (Day 57) after the last study drug administration and an end of study completion visit
(Day 71) The total duration for each subject in the study is maximum 14-weeks including
screening and baseline. No interim analysis is planned. The study design is summarized in
Figure 3-1 below for the European countries (same study design without the ketamine arm in
the USA).
Figure 3-1
Study design
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4
Rationale
4.1
Rationale for study design
The design of this study has been selected to adequately assess the primary objective and follow the 
similar design of trials for American Psychiatric Association (APA) treatment guidelines for 
depression (Practice guideline for the treatment of patients with major depressive disorder 2010)
The rationale and justification for the key elements of the study design are as follows:

Safety of administration of MIJ821 is supported by toxicology studies (i.e. 6-week GLP
studies) and by results from a study in healthy volunteers (MIJ821X2101).

Selection of ketamine 0.5 mg/kg IV infusion is a standard dose shown to have
antidepressant effects (Garay et al 2017).

Randomization to parallel groups controls for confounding factors and allows for more
valid cause judgments.

Blinding with placebo control limits effects of expectation bias or measurement bias.
The entire treatment period (36 days) can be conducted in an outpatient or inpatient treatment 
setting. Both settings are commonly used in the treatment of depression and are appropriate for 
the purpose of the study. The inpatient and outpatient setting in this study includes a frequent 
visit schedule (weekly). As the outpatient setting may increase the risk of subject suicidality, 
weekly collections of information about the suicidality risk are implemented.
For the primary objective, the efficacy will be determined using the MADRS 
(Montgomery and Asberg 1979) which is a standard for the evaluation of a major depressive 
episode.
4.2
Rationale for dose/regimen and duration of treatment
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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The use of placebo saline solution is to provide a comparison group for an unbiased collection 
and assessment of safety and tolerability data.
Ketamine is included primarily for assay sensitivity and for comparison of side effects. 
Ketamine is known to be effective with large effect sizes for severe depressive episodes, and it 
also has high rates of dissociative side effects in 20-30% of subjects, often of moderate to 
marked severity. It also can cause manic episodes, mixed states, and suicidal or aggressive 
reactions in a small minority of persons. A single subanesthetic dose of intravenous ketamine 
consistently decreases symptoms of depression in subjects with treatment-resistant depression 
in a rapid (within hours), robust (across many symptoms of depression) and relatively sustained 
(typically, 7–14 days) manner (Berman et al 2000; Cusin et al 2017). Repeated doses 
(six infusions over the course of several weeks) have shown promise from an efficacy and safety 
standpoint (Aan het Rot et al 2010). The efficacy of two times versus three times a week 
intravenous ketamine in subjects with treatment-resistant depression in sustaining the initial 
antidepressant effects was evaluated. Both doses (0.5 and 0.75 mg/kg) were significantly 
superior to placebo in treating depression symptoms and the transient dissociative side effects 
attenuated with repeat dosing (Singh et al 2016). One study examined the benefits of a fixed 
course of 4 once-weekly ketamine sessions (0.5 mg/kg IV) as continuation phase treatment in 
5 patients who had remitted after acute phase treatment. All 5 patients maintained improvement 
during the continuation phase (Krystal et al 1994).
To limit any dissociative and psychomimetic side effects, the limiting dose for Ketamine 
infusion is at 40 mg/infusion for patients over 80 kg.
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4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
There is no expected benefit for subjects participating in the study. However, in instances of 
documented TRD, participants may benefit from receiving effective antidepressant therapy to 
treat the MDD.
The risks of participating in the study include those identified in the clinical studies with MIJ821, 
those associated with IV infusion and those associated with blood sampling. The risk to subjects 
in this trial may be minimized by compliance with the eligibility criteria, specific procedures 
done by qualified personnel, study stopping rules as well as close clinical monitoring.
Subjects will 
 be observed for 2-4 hours 
(i.e. a minimum of 2 hours) after the start of infusion. If they have no dissociative symptoms 
and no suicidal symptoms after the observation period, they can leave the clinical treatment 
setting. If investigators judge that subjects have any dissociative symptoms, subjects will be 
monitored in the clinic until the dissociative symptoms resolve and/or extended stay overnight, 
or longer based on investigator judgment. 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 2-4 hours monitoring period, investigators may consider extending stay 
of subjects 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 subject to leave the 
clinical setting, but in that case arrangements should be made such that family members or 
friends are present with the subject for at least 24 hours. If such arrangements cannot be made, 
the subject may have extended stay at least overnight. If needed, an additional overnight stay 
beyond the first infusion’s baseline and V101 is permissible.
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 
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 subject will not 
reliably comply, he/she should not be entered or continue in the study.
Sexually active males must be informed of the requirement to wear a condom for the following 
reasons:

Prevent pregnancy in a female partner AND

Present delivery of investigational drug via seminal fluid to their partner as study
treatment may involve unknown risks to the fetus if pregnancy were to occur.
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Given that MIJ821 may impair the mental or physical abilities required for the performance of 
dangerous potential tasks such as driving a car or operating machinery, subjects should be 
advised about these potential risks. If the subject is feeling drunk or dizzy or if he/she 
experiences visual disturbances, hallucinations, or euphoric mood, then the subjects should not 
drive, use machines or perform any other tasks that require his/her attention and good 
coordination. In that case, the subject should be hospitalized until resolution of these events. 
These judgments will be made by the investigators, not the subjects. 
In general, hypersensitivity or infusion reaction can manifest with itching, flushing, headache, 
nausea, vomiting, hypotension, urticaria, bronchospasm, or angioedema. In the event of a 
hypersensitivity reaction, stop the infusion immediately.
Subjects participating to the MIJ821X2201 study will be provided with a subject information 
card that they would carry with them at all time and as long as they are treated with MIJ821 or 
ketamine. This card will warn of potential interaction with CYP3A4, CYP2B6, CYP2C8, 
CYP2C19, or CYP2D6 inducers or inhibitors and should be presented to every 
physician/healthcare provider the subject may consult to inform them about potential drug 
interactions. It is also important that the subject is asked to contact his/her study doctor to inform 
him/her of his/her status as well as to discuss any treatment recommendations. As a general 
precaution with all investigational drugs, sites should have the capacity of managing acute 
hypersensitivity reactions (or similar emergency situations) or be prepared to transfer the 
subject urgently, should these reactions emerge.
Benefits of ketamine have been shown for rapid improvement of depressive symptoms within 
1-2 days, which persists up to 3-4 weeks after one dose. This improvement has been shown
mainly with intravenous infusion of 0.5 mg/kg ketamine over 40 minutes (Katalinic et al 2013).
Two open-studies (Price et al 2009, Thakurta et al 2012) also have suggested that ketamine may
be an appropriate treatment to rapidly reduce acute suicide risk in depressed patients. Benefits
have been shown also recently with intranasal administration of esketamine. These benefits
occur for acute depressive symptoms, and have not been studied or proven for long-term or
maintenance administration. The amount of benefit seen acutely meets or exceeds the effect
sizes seen with standard antidepressants. Some studies report such benefit in treatment-resistant
depression, with patients who have failed multiple prior antidepressant trials. Such benefit has
been seen with both bipolar and unipolar depression.
Most of the research conducted using subanaesthetic doses of ketamine has shown 
psychotomimetic and neuropsychological adverse effects: general psychiatric symptoms, 
agitation, dissociative symptoms and manic symptoms. These effects have mostly been 
restricted to the time of administration, disappearing completely by 60 minutes afterward. 
Other adverse events experienced by patients include feelings of intoxication and lowered 
inhibitions, confusions, decreased concentration and perceptual disturbances. Most of these 
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impairments were only apparent during the infusions, and none persisted longer than 2 hours 
after the beginning of the infusions.
There have been not many significant physical adverse event reported in studies of low-dose 
ketamine (used as an antidepressant) to date. Some studies have reported a variety of non-
permanent physical effects such as light-headedness, headache, nausea, diplopia, drowsiness 
and dizziness. These symptoms tend to be benign and again limited to the period of the infusion 
or for a short time following.
Depression trials investigating subanaesthetic doses of ketamine consistently report transient 
elevations in blood pressure and heart rate during the period of infusion and for up to 80 minutes 
after dosing.
There have been a number of case reports that have linked repeated ketamine use to urinary tract 
problems. These cases have mainly been reported in the context of recreational ketamine abuse (where 
use is chronic, doses are high, and comorbidity with other substance use is common).
Finally, there are concerns about the potential for dependence through long-term or repetitive 
ketamine use. However, low-dose usage in a medical setting is less likely to produce tolerance 
(Katalinic et al 2013).
The above risks will be minimized in this trial by clinical observation during and for 2-4 hours
(i.e. a minimum of 2 hours) after the start of infusion period, as well as extended stay if needed 
based on clinical judgment at any point during the study. If severe dissociative, psychotic, 
suicidal, or agitated symptoms emerge, clinician-researchers will hospitalize research subjects 
until those clinical adverse events are resolved. If they persist, or based on clinician-researcher 
judgment or patient preference, those subjects can be dropped from the study as well at any 
time. Certain benzodiazepines, specifically lorazepam or alprazolam (as authorized by country),
administration also is allowed in the study, within dosage limitations, to manage such possible 
agitation-related effects of ketamine.
The risk of collecting blood may include fainting, pain and/or bruising: rarely, these may be a 
small blood clot or infection at the site of the needle puncture. The risks with an IV infusion 
may include pain, swelling, redness or infection at the injection site. The risk is mitigated by 
selecting professional staff from the clinic experienced in making this type of infusion.
4.5.1
Blood sample volume
A volume smaller than a typical blood donation is planned to be collected over a period of 
6 weeks, from each subject as part of the study (representing a total of around 220 ml). 
Additional samples may be required for safety monitoring.
Timing of blood sample collection is outlined in the Assessment schedule.
A summary blood log is provided in the SOM. Instructions for all sample collection, processing, 
storage and shipment information are also available in the SOM and central laboratory manual.
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5
Population
Approximately 66 subjects (66 completers for the primary endpoint) diagnosed with treatment-
resistant depression will be randomized to:
In the USA, no ketamine arm will be included. 
It will be competitive recruitment per region.
The investigator or designee must ensure that all subjects being considered for the study meet 
the following eligibility criteria.
Subject selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g. checklist) of the eligibility criteria must be stored with the source 
documentation at the study site.
Deviation from any of the entry criterion excludes a subject from enrollment into the study.
5.1
Inclusion criteria
Subjects 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 subjects, 18 to 65 years of age (inclusive) at screening.
3. SCID-based DSM-5 defined major depressive episode at the time of screening.
4. Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 24 at screening and
baseline.
5. Failure to respond to two or more antidepressant treatments, where two failed treatments
are of two different antidepressants and at least one of which is in the current depressive
episode, with adequate dose and duration (≥ 8 weeks duration, doses defined per agent), as
identified by the Maudsley Treatment Inventory, and prior psychiatric history, assessed by
the investigator, and further documented by medical records and/or third party report
(family, friends, clinician-treaters) where available
6. If patients are taking any type of psychotropic drugs, a stable dose of psychotropic drugs
at screening is defined as no changes in dose or type of antidepressants, antipsychotics, or
mood stabilizers for at least 2 weeks prior to screening, if applicable.
7. No new antidepressant initiated 4 weeks or less before baseline, and 6 weeks or less
before baseline if subject is initiated on fluoxetine
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8. At least one prior clinical depressive episode (recurrent major depressive disorder), as
identified by prior psychiatric history assessed by the investigator, and further documented
by medical records and third party report (family, friends, clinician-treaters) where
available.
9. Able to communicate well, and to understand and comply with study requirements
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Any current diagnosis of bipolar disorder, schizophrenia, or schizoaffective disorder at
screening.
2. Current alcohol or substance use disorder (including marijuana and prescribed
amphetamine)) meeting DSM-5 criteria, within the past month at baseline. Nicotine and
caffeine use disorders will not be considered as exclusionary.
3. Prior suicidality caused by or associated with ketamine, as identified by prior psychiatric
history assessed by the investigator, and augmented by medical records and third party
report (family, friends, clinician-treaters) where available.
4. Acute serious and/or imminent suicidal ideation and/or intent within the prior 2 weeks, or
any suicide attempt within the prior 4 weeks at screening. Mild to moderate suicidal
ideation, using the Sheehan Suicidal Ideation Scale and not meeting the above definition,
is not an exclusion criterion.
5. Use of other investigational drugs within 30 days or 5 half-lives of randomization,
whichever was longer; or longer if required by local regulations at baseline.
6. Current pregnancy or lactation.
7. Positive HIV, Hepatitis B or C test.
8. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment baseline
9. History of multiple and recurring allergies or allergy to the investigational
compound/compound class being used in this study.
10. History of malignancy of any organ system (other than localized basal cell carcinoma of
the skin or in-situ cervical cancer), treated or untreated, within 3 years of screening,
regardless of whether there is evidence of local recurrence or metastases.
11. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 1 week after stopping of investigational drug. 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
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment.

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
Male sterilization (at least 6 months prior to screening). For female subjects on the
study the vasectomized male partner should be the sole partner for that subject.

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of
contraception or placement of an intrauterine device (IUD) or intrauterine system
(IUS) or other forms of hormonal contraception that have comparable efficacy
(failure rate <1%), for example hormone vaginal ring or transdermal hormone
contraception
In case of use of oral contraception, women should be stable on the same pill for a 
minimum of 3 months before taking study treatment.
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 Informed Consent Form (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).
12. 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.
13. History of hypersensitivity to any of the study treatments or excipients or to drugs similar
to chemical classes that affect NMDA receptor.
14. Current diagnosis of borderline personality disorder or antisocial personality disorder,
based on DSM-5 criteria.
15. Current acute depressive episode lasting longer than two years continuously, defined as no
two week or longer period where depressive symptoms are subsyndromal in severity for a
full DSM-5 acute major depressive episode.
16. Considered by the investigator, for any other reason, to be an unsuitable candidate for the study.
General Note: In the case where a safety assessment at screening 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 subject is excluded from the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM and the Pharmacy Manual.
6.1.1
Investigational and control drugs
Table 6-1
Overview of study medication
Investigational/ Control 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Packaging
Provided by
MIJ821 20 mg
Powder for solution for 
infusion
Intravenous use
Open label bulk 
supply; vials
Novartis
Placebo
0.9% sodium chloride
Intravenous use
Open label; infusion 
bag
Novartis (EU) 
or locally by 
site (US)
Ketamine 0.5 mg/kg
limiting dose at 40 
mg/infusion for patients 
over 80 kg
Concentrate for 
solution for infusion 
Solution for injection
Intravenous use
Open label; vials
Novartis
The investigational drug MIJ821 will be available as lyophilisate in dose strength of 20 mg per 
vial. MIJ821 will be packed and labeled under responsibility of Novartis and will be supplied 
to the investigator sites. MIJ821 preparation instructions will be provided in the Pharmacy 
Manual.
The active comparator, ketamine will be provided to the investigators by Novartis and the 
placebo (saline 0.9% sodium chloride) will be sourced by Novartis (EU) or locally by site (US).
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the SOM.
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Subjects will be assigned at the baseline to one of the following 6-treatment arms in the 
European countries (5-treatment arms in the USA) in a ratio defined on the Section 5.
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6.2
Other treatment(s)
No additional treatment beyond investigational drug, comparator and placebo are included in 
this trial. 
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications / significant non-drug therapies CRF.
The risk of clinical drug-drug interaction of MIJ821 and concomitant medications has not been 
completely assessed. Based on non-clinical investigations and preliminary, qualitative risk 
estimation, appropriate caution is recommended for MIJ821 concomitantly given with 
inhibitors/inducers of CYP2D6, CYP2C19, and CYP2C8 especially CYP2D6 inhibitors like 
e.g. bupropion, fluoxetine, paroxetine, and duloxetine.
To minimize the risk of clinical drug-drug interaction, the following has to be followed:

If patients are treated with an infusion during the morning hours, they should take their
evening concomitant medications the prior night, but they should not take their morning
concomitant medications until at least two hours after the end of the infusion.

If patients are treated with an infusion from 12 noon onwards, again they should not take
their morning concomitant medications until at least two hours after the end of the
infusion.
Each concomitant drug must be individually assessed against all inclusion criteria. If in doubt 
the investigator should contact the Novartis medical monitor before randomizing a subject or 
allowing a new medication to be started. If the subject is already enrolled, contact Novartis to 
determine if the subject should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
All allowed concomitant baseline psychotropic medications must remain unchanged throughout 
the study. No new psychotropic drug should be started after baseline. All non-psychotropic 
medications should be changed as little as possible. Certain benzodiazepines, specifically
lorazepam or alprazolam (as authorized by country), will be allowed for use on an as needed 
basis for emergency agitation/anxiety, during infusion, in the morning before infusion 
(details in Section 6.2.1) and 2 hours post-infusion, not to exceed 2 mg in a 24 hour period. 
Such lorazepam or alprazolam use will be documented as concomitant medication(s).
6.2.2
Prohibited medication
There are no prohibited medications. Agents that are inhibitors/inducers of CYP2D6, CYP2C19, 
and CYP2C8 will be allowed but will be monitored carefully by the medical monitor and 
pharmacokinetics will be examined carefully. Also administration of MIJ821 and such 
CPY450 agents will not be given at the same time range.
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6.2.3
Restriction for study subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.3.1
Dietary restrictions and smoking
No dietary or smoking restrictions in this study.
6.2.3.2
Other restrictions
If the subject is feeling drunk or dizzy or if he/she experiences visual disturbances, 
hallucinations, or euphoric mood, then the subject should not drive, use machines or perform 
any other tasks that require his/her attention and good coordination.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the SOM.
6.3.2
Treatment assignment, randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider, or by a delegate under Novartis 
supervision, using a validated system that automates the random assignment of subject numbers 
to randomization numbers. These randomization numbers are linked to the different treatment 
arms.
Randomization will be stratified by region, US and European countries.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.

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Site Staff
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.6.3).
Drug product will be supplied in bulk, so an unblinded pharmacist who is independent of the 
study team will be required in order to maintain the blind. After blinded investigator or his/her 
delegate performs the randomization in NIRT system, the unblinded pharmacist will log into 
the NIRT system and see the treatment arm assigned to the randomized subject. 
Appropriate measures must be taken by the unblinded pharmacist to ensure that the treatment 
assignments are concealed from the rest of the site staff.
Sponsor Staff
The following unblinded sponsor roles are required for this study:

Unblinded field monitor(s)

Unblinded clinical staff managing drug re-supply to site

Unblinded sample analyst(s) (PK)
The unblinded field monitors are required to review drug accountability and allocation at site. 
The unblinded monitors will be unblinded through unblinded user access to the NIRT system 
and review of source documentation compiled by the unblinded pharmacist, which details 
treatment allocation to individual subjects.
Sponsor clinical staff are required to assist in the management and re-supply of investigational 
drug product. These individuals are not provided with treatment assignment directly, but may 
be unblinded through communication of drug re-supply needs via the unblinded site 
pharmacists.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the treatment assignments for interim analyses 
(if any) and is allowed to share unblinded information with the rest of the clinical team as 
appropriate for internal decision purposes, as outlined in Table 6-2. For example, unblinded 
summaries and unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis are allowed to access 
treatment assignment information for the purpose of conducting interim analyses.
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at the 
time of interim analyses while the study is ongoing.
All unblinded personnel will otherwise keep treatment allocation and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.

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Table 6-2
Blinding and unblinding plan
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Subjects
B
B
UI
Site staff
B
B
UI
Unblinded site staff e.g. 
pharmacy staff
B
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff 
e.g. for study treatment
re-supply, unblinded
monitor(s), sample
analysts (Bioanalytical
study monitor and
bioanalytical lab
personnel), Translational
Medical expert, study
leads, Clinical Trial
Associate
B
UI
UI
Unblinded 
Pharmacovigilance 
sponsor staff
B
B
UI
Statistician/statistical 
programmer/ data 
analysts (e.g.
PK)
B
B
UI
Independent committees 
used for assessing 
interim results, if required 
(e.g. DMC)
NA
NA
NA
All other sponsor staff not 
identified above (trial 
team, project team,
management & decision 
board, support functions)
B
B
UI
UI: Allowed to be unblinded on individual subject level
B: Remains blinded
NA: Not applicable to this study
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions in infusions are 
not permitted. If a subject misses a weekly dose, Novartis medical monitor must be contacted 
to determine if this subject can remain on study and continue with subsequent weekly infusions. 
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6.6
Additional treatment guidance
6.6.1
Treatment compliance
The treatment will be administered at the site. The investigator must ensure compliance by 
instructing the study personnel to deliver the study treatment exactly as prescribed and 
by stating that compliance is necessary for the subject’s safety and the validity of the study. 
Compliance will be assessed by the investigator and/or study personnel at each visit by ensuring 
that the full infusion was effectively delivered to the subject. This information should be 
captured in the source document at each visit. All study treatment dispensed and returned must 
be recorded in the Drug Accountability Log.
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with MIJ821, as detailed in the pharmacokinetics Section 8.5.2.
Please refer to the SOM and Pharmacy Manual for further details.
6.6.2
Recommended treatment of adverse events
At present there is insufficient information to provide specific recommendations regarding 
treatment of adverse events.
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant 
non-drug therapies CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the Novartis IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject 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 NIRT at any time in case of emergency. The investigator will provide:

protocol number

study drug name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time.
After an emergency code break, the subject cannot continue the study.

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6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under Section 6.1.1
(Investigational and control drugs).
For the drug preparation prior to administration, please refer to the Pharmacy Manual.
A unique medication number is printed on the study medication label.
MIJ821 will be administered to the subject via the following route of administration: i.v. 
The administration of the study treatment will occur at the study site. See the SOM and 
Pharmacy Manual for further details.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
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 subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH 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 drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject 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 subject.
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 subjects 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.
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A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF.
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Table 8-1
Assessment Schedule
Epoch
Screening
Treatment
Visit Name Screening Baseline
Treatment
Follow 
up
End 
of 
Study
Visit Numbers1
1
2
101
102 10312
104
105
106
107
108
201 202
299
Days
-28 to -2
-1 to 1
1
2
3
8
15
22
29
36
43
57
71
Time (post-dose)
-
-
0h2
1h
4h
24h
48h
0h2
2-4h
0h2
2-4h
0h2
2-4h
0h2 0.67h3 2-4h
0h2
2-4h
-
-
-
Informed consent
X
Inclusion / 
Exclusion criteria
X
X
Medical 
history/current 
medical conditions
X
Alcohol Test and 
Drug Screen 
S5
S5
Hepatitis and HIV 
Screen
S5
Pregnancy and 
assessments of 
fertility6
X7
X8
X8
X8
X7
Demography
X
Body Height
X
Body Weight
X
X
Physical 
Examination
S5
S
Vital signs and 
body 
measurements
X
X
X
X
X13
X
X
X
X13
X
X13
X
X13
X
X
X13
X
X13
X
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Epoch
Screening
Treatment
Visit Name Screening Baseline
Treatment
Follow 
up
End 
of 
Study
Visit Numbers1
1
2
101
102 10312
104
105
106
107
108
201 202
299
Days
-28 to -2
-1 to 1
1
2
3
8
15
22
29
36
43
57
71
Time (post-dose)
-
-
0h2
1h
4h
24h
48h
0h2
2-4h
0h2
2-4h
0h2
2-4h
0h2 0.67h3 2-4h
0h2
2-4h
-
-
-
Electrocardiogram 
(ECG)
X
X9
X
X
X
Hematology
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
Urinalysis
X
X
X
PK blood 
collection
X
X
X
X11
X
X
X
Dose 
administration 
(40 min)
X
X
X
X
X
X
Structured Clinical 
Interview for DSM-
5
S5
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Epoch
Screening
Treatment
Visit Name Screening Baseline
Treatment
Follow 
up
End 
of 
Study
Visit Numbers1
1
2
101
102 10312
104
105
106
107
108
201 202
299
Days
-28 to -2
-1 to 1
1
2
3
8
15
22
29
36
43
57
71
Time (post-dose)
-
-
0h2
1h
4h
24h
48h
0h2
2-4h
0h2
2-4h
0h2
2-4h
0h2 0.67h3 2-4h
0h2
2-4h
-
-
-
Maudsley 
Treatment 
Inventory
X
Sydney 
Melancholia 
Prototype Index
X
Melancholia and 
Mixed Depression 
Diagnostic 
Checklist
X
Concomitant 
therapies
X
X
X9
X
X
X
X
X
X
X
X
X
X
Montgomery-
Asberg 
Depression Rating 
Scale
X
X
X9
X
X
X
X
X
X
X
X
X
X
X
Bech Rafaelsen 
Melancholia Scale
X
X9
X 
X
X
X
X
X
X
X
X
X
X
CORE 
Melancholia Scale
X
X9
X 
X
X
X
X
X
X
X
X
X
X
Young Mania 
Rating Scale
X
X9
X 
X
X
X
X
X
X
X
X
X
Clinical Global 
Impression of 
Severity 
X
X9
X
X
X
X
X
X
X
X
X
X
X
Clinical Global 
Impression of 
Improvement
X
X
X
X
X
X
X
X
X
X
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Epoch
Screening
Treatment
Visit Name Screening Baseline
Treatment
Follow 
up
End 
of 
Study
Visit Numbers1
1
2
101
102 10312
104
105
106
107
108
201 202
299
Days
-28 to -2
-1 to 1
1
2
3
8
15
22
29
36
43
57
71
Time (post-dose)
-
-
0h2
1h
4h
24h
48h
0h2
2-4h
0h2
2-4h
0h2
2-4h
0h2 0.67h3 2-4h
0h2
2-4h
-
-
-
Clinician 
Administered 
Dissociative 
States Scale
X
X9
X
X
X
X
X
X
X
X
X
X
X
Dissociative 
Experiences Scale 
(DES)
X
X9
X
X
X
X
X
X
X
X
X
X
X
X
Generic 
Assessment of 
Side Effects in 
Clinical Trials 
(patient self-rating)
X
X9
X
X
X
X
X
X
X
X
X
X
X
Hamilton Anxiety 
Rating Scale
X
X
X
Koukopoulos 
Mixed Depression 
Rating Scale
X
X9
X
X
X
X
X
X
X
X
X
X
X
Sheehan 
Suicidality Scale
X
X
X9
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X9
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse 
Events
X
X
X9
X
X
X
X
X
X
X
X
X
X
X
X
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Epoch
Screening
Treatment
Visit Name Screening Baseline
Treatment
Follow 
up
End 
of 
Study
Visit Numbers1
1
2
101
102 10312
104
105
106
107
108
201 202
299
Days
-28 to -2
-1 to 1
1
2
3
8
15
22
29
36
43
57
71
Time (post-dose)
-
-
0h2
1h
4h
24h
48h
0h2
2-4h
0h2
2-4h
0h2
2-4h
0h2 0.67h3 2-4h
0h2
2-4h
-
-
-
Study completion 
information
X
Comments
X
X
X
X
X
X
X
X
X
X
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 Unless specified in the Assessment Schedule, all assessments are to be done before start of infusion
5 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 disorder, the subject can be enrolled.
6 Additional pregnancy testing may be performed at each visit to meet local requirements.
7 Serum pregnancy test
8 Urine pregnancy test
9 Not to be repeated if baseline visit and V101 are conducted on the same day. 
11 24 hours after start of the first infusion
12 V103 48 hours is an optional visit, however if V103 is conducted, all assessments should be completed.
13 Assessments to be conducted once between 2 and 4 hours, and at 6 hours if there is an extended stay.
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8.1
Screening
It is permissible to re-screen a subject if he/she fails initial screening. However, each case must 
be discussed and agreed with the sponsor on a case-by-case basis. There is no time frame for 
performing the re-screening tests.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the subject must be excluded from the study.
If the subject is re-screened, he/she needs to sign again a new informed consent.
Information on what data must be collected for screening failures and further information on 
re-screening is outlined in the SOM.
8.1.1
Information to be collected on screening failures
Information on what data should be collected for screening failures is outlined in the SOM.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. 
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent. Details are outlined in the SOM.
Hepatitis and HIV test will be performed for samples collected at screening 
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.3
Efficacy
8.3.1
Montgomery Asberg Depression Rating Scale
The Montgomery Åsberg Depression Rating Scale (MADRS), is a clinician-rated scale 
designed to measure depression severity and detects changes due to antidepressant treatment: 
the test consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 
(severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores 
represent a more severe condition. 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. The typical 
recall period for the MADRS is 7 days.
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8.3.4
Appropriateness of efficacy assessments
The Montgomery Åsberg Depression Rating Scale (MADRS) now is the standard scale used 
for registration studies of depression. It is relatively quick to administer (20 to 30 minutes), 
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 more sensitive to change from treatment effects over time than the Hamilton 
Depression Rating Scale (HDRS), and has replaced the latter as the gold standard registration 
scale for depression. All secondary scales are psychometrically validated and reliable as 
measures of subtypes or symptom features of depressive states. They are being used to explore 
possible subtype effects or associated symptom changes to clarify which aspects of treatment-
resistant depression may improve more or less with the interventions given. Those results will 
be descriptive and used for hypothesis generation for future studies. 
8.4
Safety / Tolerability
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 Section 10.1.1.
Assessment
Specification
Physical examination
A complete physical examination 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.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be included in the Medical 
History part of the CRF. Significant findings made after first administration 
of investigational drug which meet the definition of an Adverse Event must 
be recorded on the Adverse Event section of the CRF.
Vital sign
Vital signs include temperature, BP and pulse measurements. After the 
subject has been sitting for five minutes, with back supported and both 
feet placed on the floor, systolic and diastolic blood pressure will be 
measured three times using an automated validated device, with an 
appropriately sized cuff. The repeat sitting measurements will be made at 
1 - 2 minute intervals and the mean of the three measurements will be 
used. In case the cuff sizes available are not large enough for the 
subject's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured.
The methods, assessments, specification, and recording for each assessment will be detailed in 
the SOM.

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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.
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.
Table 8-2
Laboratory Assessments
Test Category
Test Name
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with 
differential (e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) and 
platelet count will be measured.
Chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/carbon dioxide (CO2), 
calcium, cholesterol, chloride, creatinine, creatinine kinase (CK), GGT, glucose, 
lactic dehydrogenase (LDH), inorganic phosphorus, lipase, amylase, magnesium, 
potassium, total protein, AST, ALT, sodium, triglycerides, blood urea nitrogen 
(BUN) uric acid. 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 
abnormal TSH value, additional evaluation will be performed (triiodothyronine [T3]
and thryroxine [T4]).
Urinalysis
A midstream urine sample (approximately 30 mL) will be obtained from subjects 
with no urinary catheters, 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, ketones, nitrite, leukocytes and blood. If the dipstick 
result is positive for protein, nitrite, leucocytes and/or blood, the sample will be 
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8.4.2
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.

PR interval, QRS duration, heart rate, RR interval, QT interval, QTc.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
As applicable, QTcF and QTcB may be calculated in-house. Unless auto-calculated by the ECG 
machine, the investigator must calculate QTcF at the baseline visit to assess eligibility. See the
SOM for additional details.
Clinical significant abnormalities must be reported in the AE CRF.
8.4.3
Pregnancy and assessments of fertility
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
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. A positive urine 
pregnancy test requires immediate halt of study treatment until serum β-hCG is performed and 
found to be negative.
Refer to Section 10.1.4 for details on Reporting Pregnancy.
Assessments of fertility
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 (i.e. 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 before 
taking study treatment. 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.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source, if available. 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:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required for any female 
subject, regardless of reported reproductive/menopausal status at screening.

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8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Clinical Global Impression
The Clinical Global Impression (CGI) is a 3 item observer-rated scale which measures the 
severity of symptoms, treatment response and the efficacy of treatments in treatment studies of 
patients with mental disorders (Guy 1976). CGI provides an overall clinician-determined 
summary measure that takes into account all available information, including a knowledge of 
the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the 
symptoms on the patient's ability to function. CGI is rated by an experienced clinician who is 
familiar with the disease under study and the likely progression of treatment. The CGI is rated 
without regard to the clinician's belief that any clinical changes are or are not due to medication 
and without consideration of the etiology of the symptoms.
For the study purpose 2 items will be used: the CGI-Severity, which rates illness severity, and 
the CGI-Improvement, which rates change from the initiation of treatment. The CGI-Severity 
is rated at all visit except the screening, and the CGI- Improvement at V102 and all following 
visits.
Clinical-Administered Dissociative States Scale
The Clinical-Administered Dissociative States Scale (CADSS) (Bremner et al 1998) is a 
questionnaire that assesses dissociative effects.
Each item is scored from 0 to 4 and individual scores are to be summed to obtain a total score 
ranging from a minimum of 0 to a maximum of 80. The trained staff administering the scale 
will also note their subjective interpretation of the subject's mental status and overall wellbeing, 
and whether any findings could be related to study drug.
The CADSS will be administered at all visits except the screening.
Dissociative Experiences Scale
The Dissociative Experiences Scale (DES) (Bernstein and Putnam 1986) consists of twenty-
eight questions about experiences the subject has experienced in his/her daily life. The subject 
determines to what degree he/she has been facing the situation by selecting a percentage from 
0% (never) to 100% (always), with 5% increments in between.
The DES will be administered at all visits except the screening.
Young Mania Rating Scale
The Young Mania Rating Scale (Young et al 1978) has 11 items and is based on the patient's 
subjective 
report 
of 
his/her 
clinical 
condition 
over 
the 
previous 
48 
hours. 
Additional information is based on the clinical observation made during the clinical interview.
There are 4 items that are scored from 0 to 8 (irritability, speech, thought content, and 
disruptive/aggressive behavior) and the remaining items are scored from 0 to 4.

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The Young Mania Rating Scale will be administered at all visits except screening and V103.
Bech Rafaelsen Melancholia Scale
Depression scales are used primarily to measure changes, for example, to evaluate the efficacy 
of treatment with antidepressants. The Bech-Rafaelsen Melancholia Scale (BRMS) is a 
frequently used clinician rating scale to assess the severity of depression over the past 3 days 
(Bech et al 1975). Each of the 11 BRMS items is operationally defined on a five-point scale 
(0-4); hence, the total score ranges from 0 to 44, higher scores indicating greater severity of 
depression.
The BRMS will be administered at all visits except screening.
CORE Melancholia Scale
This scale is an 18 item scale, with a 6 item component capturing cognitive impairment and two 
motoric scales capturing psychomotor retardation (7 items) and psychomotor agitation (5 items). 
A cut-off score of 8 or more has been shown to differentiate melancholic from non-melancholic 
depression, with higher scores representing a greater probability of melancholic depression. 
(Parker and McCraw 2017). 
The CORE will be administered at all visits except screening.
Maudsley Treatment Inventory
The Maudsley Treatment Inventory (MTI) is a semi-structured instrument that was developed 
to document psychotropic medications and physical therapies used in the treatment of 
depression (Fekadu et al 2018). The inventory is primarily designed for use in the current 
episode, for which treatment resistance is being rated for. However, the MTI may also be used 
for rating treatment resistance for multiple episodes.
The MTI will be administered at screening.
Generic Assessment of Side effects in Clinical Trials
The Generic Assessment of Side Effects (GASE) in Clinical Trials (Rief et al 2009) is an 
instrument to assess side effects in clinical trials. The GASE is a self-rating scale consisting of 
36 items organized by body parts. The information collected is based on the past week. GASE 
takes 5 minutes on average to be completed.
The GASE will be administered at all visits except screening.
Structured Clinical Interview for DSM-5
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for 
making the major DSM-5 diagnoses. It is administered by a clinician or trained mental health 
professional who is familiar with the DSM-5 classification and diagnostic criteria. The version 
used for this trial is the Clinician Version SCID-5-CV.The Structured Clinical Interview for 
DSM-5-Clinician Version guides the clinician step-by-step through the DSM-5 diagnostic 
process. Interview questions are provided conveniently along each corresponding DSM-5 

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criterion, which aids in rating each as either present or absent. The SCID-5-CV covers the DSM-
5 diagnoses most commonly seen in clinical settings: depressive and bipolar disorders, 
schizophrenia spectrum and other psychotic disorders, substance use disorders, anxiety 
disorders (panic disorder, agoraphobia, social anxiety disorder, generalized anxiety disorder), 
obsessive-compulsive disorder, posttraumatic stress disorder, attention-deficit/hyperactivity 
disorder, and adjustment disorder. It also screens for 17 additional DSM-5 disorders.
The SCID-5-CV will be administered at screening.
Sydney Melancholia Prototype Index
With Sydney Melancholia Prototype Index (SMPI), this diagnostic index is a one page 
assessment of two basic prototypes of depression, melancholic versus non-melancholic, each 
with 12 descriptive items. Clinicians are asked to check a box for any item which fits the patients 
description, and then to provide an overall rating about whether the patient more closely 
approximates one or the other of the two basic prototypes. (Parker and McCraw 2013).
The SMPI will be administered at screening.
Melancholia and Mixed Depression Diagnostic Checklist
With Melancholia and Mixed Depression Diagnostic Checklist (MMDC), clinicians will be 
asked to fill out a 1 ½ page form which provides a checklist for diagnostic criteria for mixed 
depression according to two different definitions, and a checklist for melancholia.  The first 
mixed depression checklist, created by Koukopoulos, has 8 criteria, which are marked as present 
or absent.  If 3 or more criteria are marked present, then mixed depression would be diagnosed. 
The second mixed depression checklist, created by Angst, lists the 7 criteria for mania from 
DSM-5, which are marked as present or absent.  If 3 or more criteria are marked present, 
excluding any duration criterion, then mixed depression would be diagnosed. The melancholia 
checklist, created by Ghaemi for this study, has 4 criteria, which are marked as present or absent.  
If 3 or more criteria are marked present, then melancholia would be diagnosed.  All of the above 
checklists occur in the presence of a DSM-5 defined major depressive episode, which is an 
inclusion criterion for this study, and would have been determined beforehand by application 
of the SCID above.
The MMDC will be administered at screening.
Hamilton Anxiety Scale
The Hamilton Anxiety Rating Scale (HAM-A) measures psychic anxiety and somatic anxiety 
symptoms based on a clinical assessment and patient interview. The scale has 14 items, with 
each item rated from 0-4, ranging from not present to very severe. A maximum score of 56 
indicates the most severe case. (Hamilton 1959).
The HAM-A will be administered at baseline, V106 and V201.

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Koukopoulos Mixed Depression Rating Scale
The Koukopoulos Mixed Depression Rating Scale (KMDRS) assesses the excitatory or mixed 
nature in patients suffering from a Major Depressive Episode (MDE) as defined by DSM-5 
criteria. This scale is meant to be used in conjunction with another scale that assess typical 
depression and anxiety symptoms. The scale contains 14 items to be evaluated by clinical 
assessment and patient interview on symptoms potentially experienced over the past week. 
Overall score increases with severity of symptoms and has a maximum score of 51. 
(Sani et al 2018).
The KMDRS will be administered at all visits except screening.
8.5.2
Pharmacokinetics
Pharmacokinetic (PK) samples will be collected at the time points defined in the 
Assessment schedule (Table 8-1). Follow instructions outlined in the SOM and in the 
Bioanalytical study specification regarding sample collection, numbering, processing and 
shipment.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the protocol.
PK samples should be collected in all patients to avoid unblinding. Only the samples from 
patients treated with MIJ821 will be analyzed
Pharmacokinetic analytical method(s)
Pharmacokinetic parameters
Commercially Confidential Information
Commercially Confidential Information

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Commercially Confidential Information

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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject's decision

Pregnancy

Any situation in which study participation might result in a safety risk to the subject

CTC-AE Grade 3 or higher adverse event unless it can be conclusively shown that AE is 
not related to study treatment.

Severe hypersensitivity reaction such as anaphylaxis

Any protocol deviation that results in a significant risk to subject safety

Adverse events, abnormal laboratory values or abnormal test result that indicate a safety 
risk to the subject
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, subjects should return for V299 and complete
the assessments indicated in the Assessment schedule for this visit. If subjects fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the subject/pre-designated contact as specified in Section 9.1.3. This contact 
should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

adverse events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section.

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9.1.1.1
Replacement policy
Subjects who are withdrawn from the study for reasons other than safety, the decision to replace 
them by an equal number of newly enrolled subjects will be taken by the Sponsor.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore
and

Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US: All biological samples not yet analyzed at the time of withdrawal may still be used for 
further testing/analysis in accordance with the terms of this protocol and of the informed consent 
form.
For EU: All biological samples not yet analyzed at the time of withdrawal will no longer be 
used, unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.

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9.1.4
Study stopping rules
The study will be stopped, and no further enrollment will take place pending a full safety review, 
if any of the following criteria are met:

At least 5 subjects in any single treatment arm experience an AE of Grade 3 or higher 
according to the CTC-AE V5.0 and is potentially related to study treatment

Two or more treatment-emergent SAEs, except those that are clearly and incontrovertibly 
due to extraneous causes;

The Sponsor considers that the number and/or severity of AEs justify putting the study on 
hold.
The study may resume following the safety review, if the Investigator and Sponsor agree it is 
safe to proceed.
9.1.5
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 subjects 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 subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a prematurely withdrawn subject. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
subject’s interests. The investigator or sponsor depending on local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their study completion 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 (e.g. each subject will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them).
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. 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 and SOM. Documentation of attempts to contact the subject should be recorded 
in the source documentation.

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10
Safety monitoring and reporting
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 subject or 
clinical investigation subject 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 subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF 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 Common Toxicity Criteria (CTC) AE grade (version 5.0 or higher). A copy of the 
CTCAE grading will be provided separately in the SOM.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0
2. its relationship to the study treatment and other investigational 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 subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved 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
5. action taken regarding with study treatment.

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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/withdrawn
6. its outcome.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
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 for at least 30 days following the last dose of 
study treatment.
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 
Investigator Brochure (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 subjects with 
the underlying disease.
Follow the instructions found in the SOM for data capture methodology regarding AE collection 
for subjects that fail screening.
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

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Life-threatening in the context of a SAE refers to a reaction in which the subject 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 inpatient 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. 

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 subject’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 subject 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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
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).
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 subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety 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.
Event common in the subject population under study: during studies, the unblinding of 
single SAEs, that are relatively common in the subject population under study, for SUSAR 
reporting, often does not increase the understanding of safety, and can damage the integrity of 
the blinded nature and analysis of a study. The study protocol may then contain a "Table of AEs 
Commonly Seen in the Subject Population" that are still captured by the investigator as AEs 
and SAEs in the CRF and reported to Novartis for the SAEs, but they would not be unblinded 

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during the course of the study, even if considered "related" to study treatment by the reporting 
investigator, nor reported on an expedited basis to regulatory authorities.
IMPORTANT: To comply with regulations, all suspected, unexpected, serious adverse 
reactions (SUSARs) occurring in a clinical trial must be reported in an expedited timeframe 
(7 or 15 days) to competent authorities.
Consider the following 2 categories to determine SAE reporting timeframes: 
1. Screen Failures (e.g. a subject who is screened but is not treated or randomized): SAEs 
occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
2. Randomized OR Treated Subjects: SAEs collected between time subject signs ICF until 
30 days after the subject has discontinued or stopped study treatment.
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 Novartis 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.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject 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. The newborns will be followed up for 3 months after delivery.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.

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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, subject 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 collected in 
the DAR (dose administration record) eCRF 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.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (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 
Section 10.1.1 and Section 10.1.2, respectively.
10.2
Additional Safety Monitoring
Not applicable.
10.2.1
Liver safety monitoring
To ensure subject 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.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 16-1 in Appendix 1 for complete definitions of liver laboratory triggers 
and liver events.

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Every liver event defined in Table 16-1 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 16-2. Repeat liver chemistry tests (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 subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results reported on the unplanned local laboratory CRF

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the subject 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
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
Refer to the SOM for additional details.
10.2.2
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

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, 
UTI, extreme exercise, or trauma)
Renal event findings must be confirmed 24-48 hours after the first assessment.
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Section 16.2.
Refer to the SOM for additional details.
10.2.3
Prospective suicidality assessment
The Sheehan Suicidality Tracking Scale is a sensitive psychometric tool to prospectively assess 
for treatment-emergent suicidal thoughts and behaviors. The Sheehan Suicidality Tracking 
Scale (Sheehan-STS) is a prospective rating scale that tracks both treatment-emergent suicidal 
ideation and behaviors. The Sheehan-STS is afourteen-item (up to 22) scale that will be 
administered by a clinician. Each item in the Sheehan-STS is scored on a 5-point Likert scale 

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(0=not at all, 1=a little, 2=moderately, 3=very, and 4=extremely). Data from the Sheehan-STS 
can be analyzed as individual item scores, suicidal ideation subscale score (sum of scores from 
items 2, 3, and 4, plus score from item 5 if ≤1), suicidal behavior subscale score (sum of scores 
from items 6, 7a, and 8, plus score from item 5 if >1), and total score.
10.2.4
Data Monitoring Committee
Not required.
11
Data Collection and Database management
11.1
Data collection
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 and 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 subject 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 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using the Novartis Interactive Response Technology (NIRT).
Each occurrence of a code break via NIRT 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.

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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. 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/delegated CRO 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 subject 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/delegated CRO/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 subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
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 
subjects will be disclosed.
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12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
12.1
Analysis sets
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS and the safety analysis set.
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 by 
system organ class and preferred term, by treatment group.
12.3
Treatments
Data for study drug administration and concomitant therapies will be summarized by treatment 
group.
Total duration of time on study drug and reasons for discontinuation of study drug will be 
summarized by treatment group.
All available data under safety analysis set will be used for reporting purpose.
12.4
Analysis of the primary endpoint(s)
The primary aim of this study is to determine whether MIJ821 displays clinical efficacy and 
safety to support further development for treatment-resistant depression.
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12.4.1
Definition of primary endpoint(s)
The primary efficacy endpoint is change from baseline in the total MADRS score at 24 h after 
single dose administration. The primary analysis will be performed on the ITT set. In addition, 
a similar analysis will be performed on the PPS.
The primary efficacy analysis may be performed once the 24-hour outcome data on MADRS 
score are available from all study participants. These results may help facilitate further planning 
activities within the MIJ821 program.
12.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in the total MADRS score at 24 hours after single dose administration 
will be analyzed using an analysis of covariance (ANCOVA) model with treatment as a group 
factor and baseline MADRS score as a covariate.
12.4.3
Handling of missing values/censoring/discontinuations
No imputation of missing data 
will be done for the primary analysis approach.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
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Supportive analyses
12.5
Analysis of secondary endpoints
12.5.1
Efficacy and/or Pharmacodynamics endpoint(s)
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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 AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on AEs will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment emergent AEs (events started after the 
first dose of 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;

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 AEs, death, SAEs, other 
significant AEs leading to discontinuation.
The incidence of psychotomimetic AEs will be tabulated by treatment group, according to 
severity and relationship to drug.
A subject with multiple AEs 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, subject, and visit/time and if ranges are 
available, abnormalities as well as clinical notable values will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time; abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
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Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
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.
Other safety evaluations
Sheehan suicidality scale score data will be listed by treatment, subject and visit/time; abnormalities 
will be flagged. Summary statistics will be provided by treatment and visit/time as appropriate.
12.5.3
Pharmacokinetics
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12.5.4
PK/PD relationships
Exposure-response analyses will be carried out for relevant endpoints measured in this study.
12.5.5
Patient reported outcomes
Not Applicable.
12.6
Analysis of exploratory endpoints
12.6.3
Other Exploratory Endpoints
12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
12.8.2
Secondary endpoint(s)
Not Applicable.
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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g., advertisements) and any other written information to be provided to subjects. Prior to 
study start, the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records to 
Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and posted 
in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 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

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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 subjects 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 implemented.
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 subject 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 subject 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
Aan het Rot M, Collins KA, Murrough JW, et al (2010) Safety and efficacy of repeated-dose 
intravenous ketamine for treatment-resistant depression. Biol. Psychiatry p. 139-45.
Bech P, Gram LF, Dein E, et al (1975) Quantitative rating of depressive states. Acta Psychiatr 
Scand p. 161-70.
Berman RM, Cappiello A, Anand A, et al (2000) Antidepressant effects of ketamine in 
depressed patients. Biol. Psychiatry p. 351-4.
Bernstein EM, Putnam FW (1986) Development, reliability, and validity of a dissociation 
scale. J. Nerv. Ment. Dis. p. 727-35.
Bremner JD, Krystal JH, Putnam FW, et al (1998) Measurement of dissociative states with the 
Clinician-Administered Dissociative States Scale (CADSS). J Trauma Stress p. 125-36.
Browne CA, Lucki I (2013) Antidepressant effects of ketamine: mechanisms underlying fast-
acting novel antidepressants. Front Pharmacol p. 161.
Cusin C, Ionescu DF, Pavone KJ, et al (2017) Ketamine augmentation for outpatients with 
treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation. 
Aust N Z J Psychiatry p. 55-64.
Eskes P, Spruit M, Brinkkemper S, et al (2016) The Sociability Score: App-based social 
profiling from a healthcare perspective. Computers in Human Behavior, 59, p. 39-48.
Fekadu A, Donocik JG, Cleare AJ (2018) Standardisation framework for the Maudsley 
staging method for treatment resistance in depression. BMC Psychiatry p. 100.
Garay RP, Zarate CA, Charpeaud T, et al (2017) Investigational drugs in recent clinical trials 
for treatment-resistant depression. Expert Rev Neurother p. 593-609.
Guy W (1976) Clinical Global Impression. ECDEU Assessment Manual for 
Psychopharmacology, revised National Institute of Mental Health, Rockville, MD..
Hamilton M (1959) The assessment of anxiety states by rating. Br J Med Psychol p. 50-5.
Isometsä ET (2001) Psychological autopsy studies--a review. Eur. Psychiatry p. 379-85.
Katalinic N, Lai R, Somogyi A, et al (2013) Ketamine as a new treatment for depression: a 
review of its efficacy and adverse effects. Aust N Z J Psychiatry p. 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.
Krystal JH, Karper LP, Seibyl JP, et al (1994) Subanesthetic effects of the noncompetitive 
NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and 
neuroendocrine responses. Arch Gen Psychiatry. 51(3) p.199–214.
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Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to 
change. Br J Psychiatry p. 382-9.
Parker G, McCraw S (2013). Validation of a new prototypic measure of melancholia. 
Comprehensive psychiatry. 54 (7) p 835-41.
Parker G, McCraw S (2017). The properties and utility of the CORE measure of melancholia. 
J of Affective Disorders. 207 p128-135
Practice guideline for the treatment of patients with major depressive disorder, third edition 
(2010).
Preskorn SH (2008) Flat dose-response curves for efficacy: what do they mean to the 
clinician? J Psychiatr Pract p. 232-6.
Price RB, Nock MK, Charney DS, et al (2009) Effects of intravenous ketamine on explicit and 
implicit measures of suicidality in treatment-resistant depression. Biol. Psychiatry p. 522-6.
Rief W, Glombiewski JA, Barsky AJ (2009) GASE: Generic Assessment of Side Effects in 
Clinical Trials p. URL: www.gase-scale.com.
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 p. 1905-17.
Sackeim HA (2001) The definition and meaning of treatment-resistant depression. J Clin 
Psychiatry p. 10-7.
Sani G, Vöhringer PA, Barroilhet SA, et al (2018) The Koukopoulos Mixed Depression 
Rating Scale (KMDRS): An International Mood Network (IMN) validation study of a new 
mixed mood rating scale. J Affect Disord p. 9-16.
Singh JB, Fedgchin M, Daly EJ, et al (2016) A Double-Blind, Randomized, Placebo-
Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-
Resistant Depression. Am J Psychiatry p. 816-26.
Thakurta RG, Das R, Bhattacharya AK, et al (2012) Rapid response with ketamine on suicidal 
cognition in resistant depression. Indian J Psychol Med p. 170-5.
Young RC, Biggs JT, Ziegler VE, et al (1978) A rating scale for mania: reliability, validity 
and sensitivity. Br J Psychiatry p. 429-35.
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16
Appendices
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY 
TRIGGERS

3 x ULN < ALT / AST < 5 x ULN

1.5 x ULN < TBL < 2 x ULN
LIVER EVENTS

ALT or AST > 5 × ULN

ALP > 2 × ULN (in the absence of known bone pathology)

TBL > 2 × 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 TBL > 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*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver
neoplasms TBL: total bilirubin; ULN: upper limit of normal

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Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study
treatment immediately

Hospitalize, if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 5 × ULN

Discontinue the study
treatment immediately

Hospitalize if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study
treatment immediately

Hospitalize, if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied by
symptomsb

Discontinue the study
treatment immediately

Hospitalize if clinically
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (subject is
asymptomatic)

Repeat LFT within the next
week

If elevation is confirmed,
initiate close observation of
the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks
ALP (isolated)
> 2 × ULN (in the absence of
known bone pathology)

Repeat LFT within 48
hours

If elevation persists,
establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit

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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (subject is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study 
treatment immediately

Hospitalize the subject

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially indicative of 
a liver toxicity*

Consider study treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values 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.

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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
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  50 % +
OR if <18 years old, eGFR < 35 
mL/min/1.73 m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected

Consider patient 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

Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected
New onset hematuria ≥ 3+ on urine 
dipstick
Assess & document

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
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology.
Whenever a renal event is identified, a detailed patient 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 edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

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

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Amended Protocol Version 02 (Clean)
Protocol No. CMIJ821X2201
Table 16-4
Renal Event Follow Up
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 cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium),
bicarbonate and uric acid

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 patient 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)
or

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