Clinical Trials Register

Summary
EudraCT Number:	2012-002954-21
Sponsor's Protocol Code Number:	KETIVEDI2001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-11-12
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

2012-002954-21

A.3

Full title of the trial

An exploratory, blinded, randomized, placebo-controlled study in subjects with depressive disorder to investigate the effect of minocycline on relapse after successful intravenous ketamine/minocycline-induced (partial) symptoms response

Estudio exploratorio, ciego, aleatorizado, controlado con placebo en sujetos con trastorno depresivo para investigar el efecto de la minociclina en recaída tras respuesta (parcial) sintomática satisfactoria inducida por ketamina intravenosa / minociclina.

A.3.1

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

The Effect of Minocycline on Relapse After Successful Intravenous Ketamine/Minocycline-induced Symptoms Response in Subjects with Depression

El efecto de la minociclina en recaída tras respuesta (parcial) sintomática satisfactoria inducida por ketamina intravenosa / minociclina

A.4.1

Sponsor's protocol code number

KETIVEDI2001

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	Janssen-Cilag International N.V.
B.1.3.4	Country	Belgium
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	Janssen Research & Development
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Janssen-Cilag International NV
B.5.2	Functional name of contact point	Clinical Registry Group
B.5.3	Address:
B.5.3.1	Street Address	Janssen Biologics BV - Clinical Registry Group - Archimedesweg 29
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333CM
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	(+)3171524 21 66
B.5.5	Fax number	(+)3171524 21 10
B.5.6	E-mail	ClinicalTrialsEU@its.jnj.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	Yes
D.2.1.1.1	Trade name	Ketamine Panpharma
D.2.1.1.2	Name of the Marketing Authorisation holder	Panpharma Laboratories
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.1	Product name	Ketamine Panpharma - solution injectable - 50 mg/5 ml
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 HYDROCHLORIDE
D.3.9.3	Other descriptive name	KETAMINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB02830MIG
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	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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Minocin
D.2.1.1.2	Name of the Marketing Authorisation holder	Teofarma Srl
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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.3.1	Product name	Minocin - hard capsule - 100 mg
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MINOCYCLINE HYDROCHLORIDE
D.3.9.1	CAS number	13614-98-7
D.3.9.3	Other descriptive name	MINOCYCLINE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB03304MIG
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	100
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	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Depressive Disorder

Trastorno depresivo

E.1.1.1

Medical condition in easily understood language

Depression

Depresión

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	PT
E.1.2	Classification code	10004940
E.1.2	Term	Bipolar II disorder
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
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

The primary objective of this study is to assess whether the antidepressant response to IV ketamine can be maintained by minocycline compared to placebo.

El objetivo principal de este estudio es determinar si la respuesta antidepresiva a la ketamina intravenosa puede mantenerse por la acción de la minociclina en comparación con un placebo.

E.2.2

Secondary objectives of the trial

To investigate the safety and tolerability of the administered study medications (i.e., ketamine and minocycline).

To investigate the effect of minocycline on symptoms of depression in ketamine non-responders.

Los objetivos secundarios de este estudio son:
Investigar la seguridad y la tolerabilidad de los fármacos del estudio administrados (es decir, ketamina y minociclina).
Investigar el efecto de la minociclina en los síntomas de depresión en pacientes que no responden a la ketamina.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Diagnostic criteria for moderate to severe major depressive disorder (MDD), without mood incongruent psychotic features, or Bipolar Disorder Type II
- Patients should have an Inventory of Depressive Symptomatology-Clinician Rated (IDS-C30) total score ? 34 at Screening and at Day 1 (predose)
- Patients with major depressive disorder should have failed at least two adequate treatment courses (dose and duration) with antidepressant therapy, one of which is in the current episode
- Patients should not have received electroconvulsive therapy (ECT) in the current episode but could be those for whom ECT is considered
- Patients with bipolar depression (BPD) Type II must have been taking a stable dose of a mood-stabilizing medication (e.g., lithium, valproate, carbamazepine, lamotrigine, antipsychotic agents) for at least 4 weeks, dosed clinically to target the therapeutic range
- Patients currently taking an antidepressant(s) must have received at least 2 weeks of stable antidepressant therapy at the time of Screening
- Doses of current antidepressant therapies should remain the same for the duration of the study
- Women must be postmenopausal, surgically sterile, or if heterosexually active, practicing a highly effective method of birth control
- Men who are heterosexually active with a woman of childbearing potential must agree to use a double barrier method of birth control and to not donate sperm during the study and for 3 months after receiving the last dose of study drug

- Criterio diagnóstico de trastorno depresivo mayor (TDM) moderado o severo, sin síntomas psicóticos incongruentes del ánimo, o trastorno bipolar tipo II.
- Los pacientes deben tener una puntuación total ≥ 34 en el Cuestionario de síntomas depresivos valorados por el médico (IDS-C30) en la visita de selección y el día 1 (antes de la administración).
- Los pacientes con TDM deben no haber respondido al menos a dos ciclos de tratamiento adecuados (dosis y duración) con un antidepresivo, uno de los cuales corresponde al episodio actual.
- No haber recibido TEC en el episodio actual, pero podría haberse considerado en ellos el uso del TEC.
- Los pacientes con TBP de tipo II deben haber estado tomando una dosis estable de un medicamento estabilizador del estado de ánimo (p. ej., litio, ácido valproico, carbamazepina, lamotrigina, antipsicóticos) durante al menos 4 semanas, en dosis clínicas para alcanzar el intervalo terapéutico.
- Los pacientes que estén recibiendo un antidepresivo deben haber recibido al menos 2 semanas de tratamiento antidepresivo estable en el momento de la selección
-Las dosis del antidepresivo actual deben ser las mismas durante todo el estudio.
- Las mujeres deben ser posmenopáusicas, estar esterilizadas quirúrgicamente, en caso de mantener relaciones heterosexuales, deben utilizar un método anticonceptivo eficaz.
- Los hombres que mantengan relaciones heterosexuales con una mujer con capacidad reproductiva deberán comprometerse a utilizar un método anticonceptivo de doble barrera y a no donar semen durante el estudio y durante 3 meses después de recibir la última dosis del fármaco del estudio.

E.4

Principal exclusion criteria

- Has a current DSM-IV axis I diagnosis other than MDD or BPD Type II at screening (except for co-morbid anxiety disorders)
- Has a diagnosis of substance abuse or dependence within 6 months prior to screening evaluation (nicotine and caffeine dependence are not exclusionary)
- Patient is currently taking ? 4 psychotropic medications at Day 1 (predose)
- Has an autoimmune disorder such as Crohn?s disease, rheumatoid arthritis, psoriasis currently treated with/requiring treatment with immunomodulatory therapies
-Has any significant cardiovascular, respiratory, neurologic, renal, hepatic, endocrine, immunologic diseases, glaucoma, hypothyroidism or hyperthyroidism based on screening examination
- Has uncontrolled hypertension (diastolic blood pressure ? 90 mmHg), despite diet, exercise or a stable dose of an allowed antihypertensive treatment, at Screening or Day 1 (predose)
- Has planned vaccination within 2 weeks prior to the first dose of study medication through 2 weeks after the last dose of study medication
- Has an active infectious disease/current infection
- Has known allergies, hypersensitivity, or intolerance to minocycline or ketamine or its excipients
- Has contraindications to the use of minocycline or ketamine per local prescribing information

-Tiene actualmente un diagnóstico del eje I del DSM-IV distinto de TDM o TBP tipo II (excepto trastornos de ansiedad comórbidos) en la visita de selección.
-Tiene antecedentes de abuso o dependencia del alcohol o de sustancias conforme a los criterios del Manual diagnóstico y estadístico de los trastornos mentales (4.a edición) (DSM-IV), excepto nicotina y cafeína, en los 6 meses previos a la visita de selección.
-Está tomando ≥ 4 psicofármacos el día 1 (antes de la administración).
-Tiene un trastorno autoinmunitario tal como la enfermedad de Crohn, artritis reumatoide o psoriasis tratado actualmente con inmunomoduladores o que requiere inmunomoduladores.
-Tiene una enfermedad cardiovascular, respiratoria, neurológica, renal, hepática, endocrina, inmunológica importante, glaucoma, hipotiroidismo o hipertiroidismo conforme a la exploración de selección.
-Padece hipertensión no controlada (presión arterial diastólica ≥ 90 mm Hg), a pesar de controlar la dieta, hacer ejercicio o tomar una dosis estable de un antihipertensivo permitido, en la visita de selección o el día 1 (antes de la administración).
-Tiene previsto vacunarse desde 2 semanas antes de la primera dosis de la medicación del estudio hasta 2 semanas después de la última dosis de la medicación del estudio.
-Tiene una enfermedad infecciosa activa/infección actual.
-Padece alergias, hipersensibilidad o intolerancia conocidas a la minociclina, a la ketamina o a sus excipientes.
-Tiene contraindicaciones para el uso de minociclina o ketamina conforme a la ficha técnica local.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint will be the proportion of subjects who survive relapse-free (among responders).

El criterio de valoración principal de la eficacia será la proporción de pacientes que sobrevivan sin recaídas (entre los pacientes con respuesta)

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 54 (Week 6) of the 6-week blinded treatment period.

Dia 54 (Semana 6) de las 6 semanas de tratamiento ciego

E.5.2

Secondary end point(s)

1. The change in MADRS total score among non-responders from pre-randomization to end-of-study.
2. Change in the MADRS total score from baseline during the IV ketamine treatment phase.
3. Change in the MADRS total score from baseline after IV ketamine treatment phase.
4. Response (reduction ? 50% in MADRS total score relative to baseline) rate during the IV ketamine treatment phase.
5. Time to relapse (among responders) following completion of the IV ketamine infusion schedule .
6. Change in Columbia Suicide Severity Rating Scale (C-SSRS).

1 Cambio de la puntuación total de la escala MADRS entre los pacientes que no respondan desde pre-aleatorización hasta el final del estudio.
2 Cambio de la puntuación total de la escala MADRS con respecto al valor basal (día 1 antes de la administración) durante la fase de tratamiento con ketamina intravenosa.
3 Cambio de la puntuación total de la escala MADRS con respecto al valor basal (día 1 antes de la administración) después de la fase de tratamiento con ketamina intravenosa.
4 Tasa de respuesta (reducción ≥ 50% de la puntuación total de la escala MADRS con respecto al valor basal) durante la fase de tratamiento con ketamina intravenosa.
5 Tiempo hasta la recaída (entre los pacientes con respuesta) después de la finalización de la pauta de infusión de ketamina intravenosa.
6 Efectos sobre la escala de valoración de la gravedad de la conducta suicida de Columbia (C-SSRS)

E.5.2.1

Timepoint(s) of evaluation of this end point

1. From Day 12 to Day 54.
2. Days 1, 3, 5, 8, 10, and 12.
3. Days 1, 20, 27, 34, 41, 48, and 54.
3. Days 1, 3, 5, 8, 10 and 12.
4. Day 12 to Day 54.
5. Day 1, 12 & 54.

1. Desde día 12 a día 54
2. Días 1, 3, 5, 8, 10, y 12.
3. Días 1, 20, 27, 34, 41, 48, y 54.
3. Días 1, 3, 5, 8, 10 y 12.
4. Día 12 a día 54.
5. Día 1, 12 y 54.

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

E.6.7

Pharmacodynamic

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

Yes

E.6.13.1

Other scope of the trial description

Biomarker Marker Analysis

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

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)

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

Belgium

France

Moldova, Republic of

Netherlands

Spain

Romania

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

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)

Yes

F.1.3.1

Number of subjects for this age range:

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)

All subjects can return to standard of care treatment following the End-of-Study (EOS) visit.

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

2014-01-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-10

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-07-10

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