Clinical Trials Register

Summary
EudraCT Number:	2010-024165-44
Sponsor's Protocol Code Number:	CSOM230B2406
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:	2011-07-07
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

2010-024165-44

A.3

Full title of the trial

Estudio abierto, multicéntrico, de acceso expandido de pasireotida s.c., en pacientes con enfermedad de Cushing

A.3.1

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

Estudio en el que se sabe qué fármaco toma cada paciente, llevado a cabo en varios hospitales, con Pasireotida subcutánea en pacientes con enfermedad de Cushing

A.4.1

Sponsor's protocol code number

CSOM230B2406

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 FARMACEUTICA 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 Farmaceútica
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Javier Malpesa
B.5.2	Functional name of contact point	Javier Malpesa
B.5.3	Address:
B.5.3.1	Street Address	C/ Gran Via de les Corts Catalanes, 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Seychelles
B.5.4	Telephone number	+34933064464
B.5.5	Fax number	+34933064615
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/671
D.3 Description of the IMP
D.3.1	Product name	Pasireotida 300
D.3.2	Product code	SOM230
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pasireotida
D.3.9.2	Current sponsor code	SOM230B
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/671
D.3 Description of the IMP
D.3.1	Product name	Pasireotida 600
D.3.2	Product code	SOM230B
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pasireotida 600
D.3.9.1	CAS number	SOM230B
D.3.9.2	Current sponsor code	SOM230B
D.3.9.3	Other descriptive name	SOM230B
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
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: 3
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/09/671
D.3 Description of the IMP
D.3.1	Product name	Pasireotida 900
D.3.2	Product code	SOM230B
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pasireotida 900
D.3.9.1	CAS number	SOM230B
D.3.9.2	Current sponsor code	SOM230B
D.3.9.3	Other descriptive name	SOM230B
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	900
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Enfermedad de Cushing

E.1.1.1

Medical condition in easily understood language

Enfermedad de Cushing

E.1.1.2

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	SOC
E.1.2	Classification code	10014698
E.1.2	Term	Endocrine disorders
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10011651
E.1.2	Term	Cushing's disease
E.1.2	System Organ Class	10014698 - Endocrine disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Documentar la seguridad de pasireotida s.c. en pacientes con enfermedad de Cushing.

E.2.2

Secondary objectives of the trial

Documentar la eficacia de pasireotida s.c. en la normalización del UFC en la Semana 12 y 24, por separado.
Documentar la eficacia de pasireotida s.c. para alcanzar por lo menos una reducción del 50% del UFC, respecto al valor basal, en la semana 12 y 24, por separado
Documentar los cambios en los signos y síntomas clínicos
Documentar los cambios en los cuestionarios de resultados notificados por el paciente (WPAI-GH y QoL de Cushing).
Documentar los efectos de pasireotida s.c. en el eje GH/IGF-I.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Consentimiento informado por escrito obtenido antes de cualquier procedimiento de selección
2. Pacientes varones o mujeres con 18 años de edad o más.
3. Pacientes con diagnóstico confirmado de enfermedad de Cushing, demostrado por:
nivel medio de cortisol libre en orina de tres muestras de orina de 24 horas recogidas durante el periodo de selección de 3 semanas, por encima del límite superior del valor normal del laboratorio
niveles de ACTH en plasma matutinos dentro de su valor normal o por encima de éste.
confirmación con RM de adenoma hipofisario (mayor o igual a 0.6 cm), o gradiente del seno petroso inferior > 3 tras la estimulación con CRH para pacientes con un microadenoma menor de 0.6 cm* o para pacientes que hayan sido sometidos a una cirugía hipofisaria previa, histopatología que confirme la presencia de un adenoma con tinción de ACTH. (*si la IPSS se ha realizado previamente sin CRH (por ejemplo, con DDAVP), entonces se requiere un gradiente pre-estimulación central-periférico > 2. Si la IPSS no se ha realizado previamente, se requiere IPSS con estimulación de CRH.
4. Los pacientes con enfermedad de Cushing de novo no deberán considerarse como candidatos para cirugía hipofisaria (es decir, candidatos no apropiados para la cirugía, tumores inaccesibles quirúrgicamente, pacientes sin tumor hipofisario visible, pacientes que se nieguen a recibir tratamiento quirúrgico).
5. Estado funcional de Karnofsky > 60% (es decir, requiere ayuda ocasional, pero puede atender a la mayoría de sus necesidades personales).
6. Para los pacientes en tratamiento médico previo para la enfermedad de Cushing, los siguientes periodos de lavado se deberán completar antes de realizar las evaluaciones de selección:
Inhibidores de la estereoidogénesis (ketoconazol, metirapona, rosiglitazona): 1 semana.
Agonistas dopaminérgicos (bromocriptina, cabergolina): 4 semanas.
Octreótida LAR y Lanreótida Autogel: 8 semanas.
Lanreótida SR: 4 semanas.
Octreótida (formulación de liberación inmediata): 1 semana

E.4

Principal exclusion criteria

1. Radioterapia hipofisaria < 4 semanas antes de la selección o paciente que no se haya recuperado de los efectos secundarios
2. Pacientes con compresión del quiasma óptico que les produce defecto del campo visual clínicamente significativo.
3. Pacientes con síndrome de Cushing por secreción ectópica de ACTH.
4. Pacientes con hipercortisolismo secundario a tumores suprarrenales o a hiperplasia nodular suprarrenal bilateral (primaria).
5. Pacientes con un síndrome hereditario conocido como la causa de hipersecreción hormonal (es decir, Complejo de Carney, síndrome de McCune-Albright, MEN-1).
6. Pacientes con diagnóstico de aldosteronismo sensible a glucocorticoides (GRA).
7. Pacientes sometidos a una cirugía mayor en el plazo de 1 mes antes del inicio de la selección.
8. Pacientes con colelitiasis sintomática.
9. Pacientes diabéticos cuya glucemia no está bien controlada, demostrado por una HbA1c > 8%.
10. Pacientes con deterioro clínicamente significativo de la función cardiovascular o con riesgo de ello, demostrado por
pacientes con insuficiencia cardiaca congestiva (clase III o IV de la NYHA), angina inestable, taquicardia ventricular prolongada, bradicardia clínicamente significativa, bloqueo AV de grado elevado, antecedentes de IM menos de un año antes del inicio del estudio
QTcF >450 ms en la visita de selección
Antecedentes de síncope o antecedentes familiares de muerte súbita idiopática
Factores de riesgo de Torsades de Pointes como hipocalemia no corregida, hipomagnesemia no corregida, insuficiencia cardíaca
Enfermedad(es) concomitante(s) que puedan prolongar el intervalo QT como neuropatía autonómica (causada por diabetes o enfermedad de Parkinson), VIH, cirrosis, hipotiroidismo incontrolado, medicación(es) concomitante(s) que se conozca(n) que aumentan el intervalo QT
11. Pacientes con enfermedad hepática, como cirrosis, hepatitis crónica activa o hepatitis crónica persistente, o pacientes con niveles de ALT/AST > 2 x LSN, de creatinina sérica > 2.0 x LSN, de bilirrubina sérica > 2.0 x LSN y de albúmina sérica < 0.67 x LIN
12. Pacientes con algún trastorno médico actual o previo que pueda interferir con la realización del estudio o la evaluación de sus resultados, como
Antecedentes de inmunocompromiso, incluido un resultado de positividad del VIH (Elisa y Western blot). No se requerirá una prueba de detección de VIH, sin embargo, se revisará el historial clínico previo
Presencia de infección incontrolada crónica o aguda sospechada o activa
Antecedentes de alcoholismo en el periodo de 6 meses previo a la selección
13. Pacientes embarazadas o en periodo de lactancia, o en edad fértil que no utilicen un método anticonceptivo clínicamente aceptable. Si una mujer está participando en el ensayo, entonces es suficiente un método anticonceptivo (píldora o diafragma) y la pareja debería utilizar un preservativo. Si se utilizan anticonceptivos orales además de preservativos, la paciente deberá haber practicado este método durante por lo menos dos meses antes de la selección y deberá acceder a continuar con el anticonceptivo oral durante todo el transcurso del estudio y durante 3 meses después de que el estudio haya finalizado. Los pacientes varones sexualmente activos deberán usar preservativos durante todo el estudio y durante tres meses después como una medida de precaución (los datos no disponibles no indican ningún aumento del riesgo reproductor con las medicaciones del estudio).
14. Pacientes que hayan participado en alguna investigación clínica con un fármaco en investigación durante el mes previo a la selección o pacientes que hayan sido tratados previamente con pasireotida.
15. Pacientes con hipersensibilidad conocida a los análogos de la somatostatina.
16. Pacientes con antecedentes de incumplimento con regímenes médicos o que se consideren potencialmente no fiables o incapaces de completar todo el estudio.

E.5 End points

E.5.1

Primary end point(s)

Proporción de pacientes que tienen efectos adversos relacionados con el fármaco de grado 3 o 4 o descritos como efectos adversos serios.

E.5.1.1

Timepoint(s) of evaluation of this end point

No se ha previsto realizar ningún análisis intermedio formal. Sin embargo, ya que la fecha de aprobación del fármaco puede diferir entre regiones, los datos de una región específica pueden presentarse cuando todos los pacientes de dicha región hayan sido controlados durante 28 días después de que hayan suspendido prematuramente pasireotida s.c. o después de finalizar el tratamiento según el protocolo (es decir, cuando la medicación del estudio se comercialice en cada país respectivo o un año después de la FPFV en cada país respectivo, lo que ocurra primero).
No se han previsto adaptaciones del diseño.

E.5.2

Secondary end point(s)

E.5.2.1

Timepoint(s) of evaluation of this end point

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

Information not present in EudraCT

E.8.1.2

Open

Information not present in EudraCT

E.8.1.3

Single blind

Information not present in EudraCT

E.8.1.4

Double blind

Information not present in EudraCT

E.8.1.5

Parallel group

Information not present in EudraCT

E.8.1.6

Cross over

Information not present in EudraCT

E.8.1.7

Other

Information not present in EudraCT

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Argentina

Brazil

Czech Republic

Egypt

Germany

Greece

Hungary

Korea, Republic of

Netherlands

Romania

Spain

Thailand

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

Patients will be treated until the drug becomes commercially available in each respective country or up to one year after FPFV in each respective country, whichever occurs first.

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

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

Yes

F.3.3.2

Women of child-bearing potential using contraception

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

200

F.4.2.2

In the whole clinical trial

300

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)

Should pasireotide not be available to patients in each respective country, Novartis will have a local transition plan in order to ensure that all trial patients will still have access to the study medication without any delay in their treatment. End of the study will thus be reached once LPLV (28 days after the last dose) in the last participating country has occurred.

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

2011-08-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-08-05

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-01-26

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