Clinical Trials Register

Summary
EudraCT Number:	2018-003002-12
Sponsor's Protocol Code Number:	CMIJ821X2201
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-04-12
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2018-003002-12

A.3

Full title of the trial

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

Estudio de fase II, multicéntrico, aleatorizado, ciego para el sujeto y el investigador, controlado con placebo, con comparador activo y de grupos paralelos para evaluar la eficacia, seguridad, tolerabilidad y farmacocinética de MIJ821 en pacientes con
depresión resistente al tratamiento

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy, safety, tolerability, and pharmacokinetics of MIJ821 in
patients with treatment-resistant depression

Estudio de eficacia, seguridad, tolerabilidad y farmacocinética de MIJ821 en pacientes con depresión resistente al tratamiento.

A.3.2

Name or abbreviated title of the trial where available

Study of efficacy and safety of MIJ821 in treatment-resistant depression patients

Estudio de eficacia y seguridad de MIJ821 en pacientes con depresión resistente al tratamiento.

A.4.1

Sponsor's protocol code number

CMIJ821X2201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03756129

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Farmacéutica, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmácéutica, S.A.
B.5.2	Functional name of contact point	TMo
B.5.3	Address:
B.5.3.1	Street Address	Gran Vía de les Corts Catalanes 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34933064464
B.5.5	Fax number	NANANA
B.5.6	E-mail	eecc.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.2	Product code	MIJ821
D.3.4	Pharmaceutical form	Lyophilisate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not available yet
D.3.9.3	Other descriptive name	MIJ821
D.3.9.4	EV Substance Code	SUB195330
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	KETOLAR
D.2.1.1.2	Name of the Marketing Authorisation holder	Parke-Davis, S.L. – Grupo PFIZER
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	KETAMINE
D.3.9.1	CAS number	6740-88-1
D.3.9.4	EV Substance Code	SUB08365MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment Resistant Depression

Depresión resistente al tratamiento

E.1.1.1

Medical condition in easily understood language

Depression

Depresión

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Psychological processes [F02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10057840
E.1.2	Term	Major depression
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess efficacy of MIJ821 in treatment resistant depression

Evaluar la eficacia de MIJ821 en la depresión resistente al tratamiento.

E.2.2

Secondary objectives of the trial

To assess risk of mania induction
To assess efficacy in the melancholic subtype of depression
To assess safety and tolerability, especially dissociative side effects
To assess most effective dose and dosing regimen
To assess MIJ821 pharmacokinetics in plasma
To assess impact of MIJ821 on suicidality
To assess efficacy of MIJ821 on measures of Response
To assess efficacy of MIJ821 on measures of Remission
To assess efficacy of MIJ821 for mixed mood Symptoms
To assess efficacy of MIJ821 for anxiety Symptoms
To assess the impact of anxiety as predictor of treatment response to MIJ821
To assess the impact of Melancholia as predictor of treatment response to MIJ821
To assess the impact of Mixed Mood symptoms as predictor
of treatment response to MIJ821

Evaluar el riesgo de inducción maníaca
Evaluar la eficacia en el subtipo de depresión melancólica.
Evaluar la seguridad y tolerabilidad, especialmente los efectos secundarios disociativos.
Evaluar la dosis y la pauta posológica más efectivas.
Evaluar la farmacocinética de MIJ821 en plasma.
Evaluar el impacto de MIJ821 sobre las tendencias suicidas.
Evaluar la eficacia de MIJ821 en medidas de respuesta.
Evaluar la eficacia de MIJ821 en medidas de remisión.
Evaluar la eficacia de MIJ821 para los síntomas mixtos del estado de ánimo.
Evaluar la eficacia de MIJ821 en síntomas de ansiedad.
Evaluar el impacto de la ansiedad como predictor del tratamiento en respuesta al MIJ821.
Evaluar el impacto de la melancolía como predictor del tratamiento en respuesta al MIJ821
Evaluar el impacto de los síntomas mixtos del estado de ánimo como predictor del tratamiento en respuesta al MIJ821

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Signed informed consent.
- Male and female subjects, 18 to 65 years of age
(inclusive) at screening.
- DSM-5 defined major depressive episode at the time
of screening
- Montgomery-Åsberg Depression Rating Scale
(MADRS) score ≥ 24 at baseline
- Failure to respond to two or more antidepressant
treatments, at least one of which is in the current
depressive episode, with adequate dose and duration.
- Stable dose of psychotropic drugs at screening
defined as no changes in dose or type of
antidepressants, antipsychotics, or mood stabilizers
for at least 2 weeks prior to randomization if applicable.
- No new antidepressant initiated 4 weeks or less
before baseline, and 6 weeks or less before baseline if
subject is initiated on fluoxetine
- At least one prior clinical depressive episode
(recurrent major depressive disorder).
- Able to communicate well, and to understand and
comply with study requirements

- Se deberá obtener el consentimiento informado firmado
- Sujetos de ambos sexos con edades comprendidas entre los 18 y los 65 años (ambos incluidos) en la selección.
- Sujetos con un episodio depresivo mayor DSM-5 en el momento de la selección.
- Sujetos con una puntuación ≥24 en la escala Montgomery-
Åsberg Depression Rating Scale (MADRS) en la basal.
- Falta de respuesta a dos o más tratamientos antidepresivos previos con dosis y duración adecuadas para un episodio depresivo mayor actual
-Una dosis estable de fármacos psicotrópicos en la selección definida como sin cambios en la dosis o tipo de antidepresivos, antipsicóticos o estabilizadores del estado de ánimo durante al menos 2 semanas antes de la aleatorización, si corresponde.
-No iniciar un nuevo antidepresivo 4 semanas o menos antes de la basal, y si el sujeto comienza con fluoxetina 6 semanas o menos antes de la basal.
- Al menos un episodio depresivo clínico previo (trastorno depresivo mayor recurrente)
-Poder comunicarse bien y entender y cumplir los requisitos del estudio.

E.4

Principal exclusion criteria

- Any prior or current diagnosis of bipolar disorder,
schizophrenia, or schizoaffective disorder at screening.
- Current alcohol or substance use (other than nicotine
or caffeine) meeting DSM-5 criteria for addiction,
within the past month.
- 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.
- Use of other investigational drugs at the time of
randomization, or within 30 days or 5 half-lives of
randomization, whichever was longer; or longer if
required by local regulations at baseline.
- Current pregnancy or lactation.
- Positive HIV, Hepatitis B or C test.
- Resting QTcF ≥450 msec (male) or ≥460 msec
(female) at pre-treatment baseline
- History of multiple and recurring allergies or allergy to
the investigational compound/compound class being
used in this study.
- History of malignancy of any organ system (other
than localized basal cell carcinoma of the skin or insitu
cervical cancer), treated or untreated, within the
past 3 years, regardless of whether there is evidence
of local recurrence or metastases.
- Women of child-bearing potential, defined as all
women physiologically capable of becoming pregnant,
unless they are using highly effective methods of
contraception during dosing and for 1 week after
stopping of investigational drug.
- History of hypersensitivity to any of the study
treatments or excipients or to drugs similar to chemical
classes.
- Current diagnosis of borderline personality disorder
or antisocial personality disorder, based on DSM-5
criteria.
- Current acute depressive episode lasting longer than
two years continuously, defined as no two week or
longer period where depressive symptoms are
subsyndromal in severity for a full DSM-5 acute major
depressive episode.
- Considered by the investigator, for any other reason,
to be an unsuitable candidate for the study.

- Cualquier diagnóstico previo o actual de trastorno bipolar, esquizofrenia o trastorno esquizoafectivo
- Consumo de alcohol o drogas (excepto nicotina o cafeína) que cumplan los criterios DSM-5 de adicción durante el último mes.
- Tendencias suicidas previas causadas o asociadas a ketamina, identificadas mediante antecedentes psiquiátricos evaluadas por el investigador y confirmadas mediante historias clínicas o informes de terceros (familiares, amigos, médicos responsables del tratamiento), cuando proceda.
-Ideación suicida o intento de suicidio agudo, grave y/o inminente durante las 2 semanas anteriores o cualquier intento de suicidio durante las 4 semanas anteriores a la selección.
- Uso de otros fármacos en investigación en el momento de la inclusión, o durante los 30 días o 5 semividas anteriores a la inclusión, aquello que sea más largo, o durante más tiempo si así lo exige la normativa local.
- Embarazo o lactancia actuales
- Resultado positivo en la prueba del VIH, hepatitis B o hepatitis C.
- QTcF en reposo ≥450 mseg (varones) o ≥460 mseg (mujeres)
en la basal previa al tratamiento.
-Antecedentes de alergias múltiples y recurrentes o alergia a la clase de compuesto/compuesto en investigación que se utiliza en este estudio.
Antecedentes de tumor maligno de cualquier sistema orgánico (salvo carcinoma basocelular localizado de la piel o cáncer de cuello uterino in situ), tratado o no tratado, durante los últimos 3 años, independientemente de que existan o no pruebas de recurrencia local o metástasis.
Mujeres en edad fértil, definidas como toda mujer fisiológicamente capaz de quedarse embarazada, salvo que esté utilizando métodos anticonceptivos altamente eficaces durante la administración de la dosis y durante 1 semana después de finalizar el fármaco en investigación.
Antecedentes de hipersensibilidad a alguno de los tratamientos del estudio o sus excipientes o a fármacos de clases químicas similares.
-Diagnóstico actual de trastorno límite de personalidad o trastorno antisocial de la personalidad, según los criterios DSM-5.
-Episodio depresivo agudo actual que dure más de dos años de manera continuada, es decir, que no haya presentado un periodo de dos semanas o más en el que los síntomas depresivos hayan sido de intensidad subsindromica para un episodio depresivo mayor agudo que cumpla todos los criterios de DSM-5.
-Aquel sujeto que el investigador considere, por cualquier otro motivo, que es un candidato inadecuado para el estudio
.

E.5 End points

E.5.1

Primary end point(s)

Total score of MADRS

Puntuación total de la MADRS

E.5.1.1

Timepoint(s) of evaluation of this end point

24 hours after start of the infusion compared to baseline assessment

24 horas después del comienzo de la infusión comparado con la evaluación basal.

E.5.2

Secondary end point(s)

Young Mania Rating Scale
Bech-Rafaelsen melancholia scale
Clinician-Administered Dissociative States Scale
Dissociative Experiences Scale
Montgomery Åsberg Depression Rating Scale (MADRS)

-Escala de Young para la evaluación de la manía
-Escala de evaluación de la melancolía de Bech-Rafaelsen.
-Escala clínica administrada para estados disociativos
-Escala de experiencias disociativas
-Escala de Montgomery Åsberg para la evaluación de la Depresión

E.5.2.1

Timepoint(s) of evaluation of this end point

24 hours, 48 hours and 6 weeks
Change from baseline to 24 hours, 48 hours and 6 weeks
Score at 6 weeks

24 horas, 48 horas y 6 semanas
Cambio desde basal de 24 horas, 48 horas y 6 semanas
Puntuación a las 6 semanas

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Czech Republic

Spain

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Ultima visita del ultimo paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Ninguno

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-04-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-03-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-03-23

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