Clinical Trials Register

Summary
EudraCT Number:	2012-000083-24
Sponsor's Protocol Code Number:	0624-206
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:	2012-03-29
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

2012-000083-24

A.3

Full title of the trial

A PHASE 2, RANDOMIZED, DOUBLE-BLIND, MULTICENTER, DOSERANGING, CROSSOVER STUDY TO EVALUATE THE SAFETY AND EFFICACY OF SUBCUTANEOUS ADMINISTRATION OF CINRYZE® (C1 ESTERASE INHIBITOR [HUMAN]) WITH RECOMBINANT HUMAN HYALURONIDASE (rHuPH20) FOR THE PREVENTION OF ANGIOEDEMA ATTACKS IN ADOLESCENTS AND ADULTS WITH HEREDITARY ANGIOEDEMA

ESTUDIO MULTICÉNTRICO DE FASE 2, ALEATORIZADO, DOBLE CIEGO, DE RANGO DE DOSIS Y CRUZADO, PARA EVALUAR LA SEGURIDAD Y LA EFICACIA DE LA ADMINISTRACIÓN SUBCUTÁNEA DE CINRYZE®
(INHIBIDOR DE LA ESTERASA C1 [HUMANO]) CON HIALURONIDASA HUMANA RECOMBINANTE (rHuPH20) PARA LA PREVENCIÓN DE LAS CRISIS DE ANGIOEDEMA EN ADOLESCENTES Y ADULTOS CON ANGIOEDEMA HEREDITARIO

A.3.1

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

A Study of the Safety and Efficacy of Subcutaneous Administration of Cinryze with Recombinant Human Hyaluronidase for the Prevention of HAE Attacks

Un estudio de seguridad y eficacia de la administración subcutánea de Cinryze con hialuronidasa humana recombinante para la prevención de crisis de angioedema hereditario.

A.4.1

Sponsor's protocol code number

0624-206

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	ViroPharma Incorporated
B.1.3.4	Country	United States
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	ViroPharma SPRL
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	Viropharma SPRL
B.5.2	Functional name of contact point	Danielle Tierens
B.5.3	Address:
B.5.3.1	Street Address	Rue Montoyer 47
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+32027470971
B.5.5	Fax number	+32027062421
B.5.6	E-mail	danielle.tierens@viropharma.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	Cinryze
D.2.1.1.2	Name of the Marketing Authorisation holder	Viropharma SPRL
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Powder and solvent for 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.3.9.3	Other descriptive name	INHIBIDOR DE LA ESTERASA C1 COMPLEMENTO
D.3.9.4	EV Substance Code	SUB22696
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Angioedema.

E.1.1.1

Medical condition in easily understood language

Symptoms or signs such as swelling or pain at any location.

Síntomas o indicios como edema o dolor en cualquier lugar.

E.1.1.2

Therapeutic area

Body processes [G] - Genetic Phenomena [G05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10019860
E.1.2	Term	Hereditary angioedema
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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 evaluate the efficacy of two doses of CINRYZE with rHuPH20 administered by SC injection to prevent HAE attacks.
To assess the safety and tolerability of two doses of CINRYZE with rHuPH20 administered by SC injection.

Evaluar la eficacia de dos dosis de CINRYZE con rHuPH20 administradas por inyección SC para prevenir las crisis de AEH.
Evaluar la seguridad y la tolerabilidad de dos dosis de CINRYZE con rHuPH20 administradas por inyección SC.

E.2.2

Secondary objectives of the trial

To determine the optimal dose of CINRYZE with rHuPH20 administered by SC injection for prevention of angioedema attacks based upon benefit-risk assessment.
To further characterize the PK and PD of CINRYZE with rHuPH20 administered by SC injection.
To assess the immunogenicity of CINRYZE with rHuPH20 following SC administration.
To assess subject acceptance of SC administration of CINRYZE with rHuPH20 for prevention of angioedema attacks.
To assess health status (quality of life) of this patient population.

Determinar la dosis óptima de CINRYZE con rHuPH20 administrado por inyección SC para la prevención de las crisis de angioedema basándose en la valoración de la relación beneficio-riesgo.
Definir mejor la FC y la FD de CINRYZE con rHuPH20 administrado mediante inyección SC.
Valorar la inmunogenicidad de CINRYZE con rHuPH20 tras la administración SC.
Valorar la aceptación de los sujetos a la administración SC de CINRYZE con rHuPH20 para la prevención de las crisis de angioedema.
Valorar el estado de salud (calidad de vida) de esta población de pacientes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

To be eligible for this protocol, a subject must:
Be >=12 years of age.
Have a confirmed diagnosis of HAE with a history of at least one of the following:
C1 INH antigen level below normal; Functional C1 INH level below normal; If currently receiving prophylactic IV CINRYZE therapy (i.e., 1000 U every 3 or days or up to 2000 U per week), have: during the 3 consecutive months prior to randomization, an HAE attack rate of <=1.0 moderate or severe attack per month (average). During the 3 consecutive months prior to starting prophylactic IV CINRYZE therapy, a history of at least 2.0 moderate or severe HAE attacks per month (average).
If not on prophylactic IV CINRYZE therapy, have a history of at least 2.0
moderate or severe HAE attacks per month (average) during the 3 consecutive
months prior to randomization.
Agree to avoid his/her known HAE triggers during the study to the best of his/her ability.
Agree to adhere to the protocol-defined schedule of assessments and procedures. If female, be post-menopausal (cessation of menses greater than or equal to 1 year), surgically sterile, or following an acceptable non-hormonal method of birth control such as intrauterine device or barrier control for at least 1 complete menstrual cycle before the screening visit and agree to continue use through the 30-day post-treatment visit, or using hormonal birth control products for at least 3 months prior to the first dose of study drug in Treatment Period 1 and agree to continue use through the 30-day post-treatment visit. If male, be surgically sterile or agree to follow an acceptable method of birth control (e.g., barrier control) from the screening visit through 2 months after the last dose of study drug. If an adult (>=18 years of age), be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
If a child (<18 years of age), have a parent(s)/legal guardian who is informed of the nature of the study provide written informed consent for the child to participate in the study before any study-specific procedures are performed (with assent from the child when appropriate). Alternatively, certain sites/IRAs may permit adolescents who are <18 years of age to be informed of the nature of the study and provide written informed consent without consent from a parent(s)/legal guardian.

Para poder participar en este protocolo, los sujetos deberán:
1. Tener >= 12 años de edad.
2. Tener un diagnóstico confirmado de AEH con al menos uno de los antecedentes siguientes:
- Concentración de antígeno del INH C1 inferior a la normal
- Concentración del INH C1 funcional inferior a la normal
3. Si están recibiendo actualmente tratamiento profiláctico con CINRYZE IV (es decir, 1000 U cada 3 ó 4 días o hasta 2000 U a la semana), deben tener:
- durante los 3 meses consecutivos previos a la aleatorización, una tasa de crisis de AEH de <= 1,0 crisis moderadas1 o intensas2 al mes (en promedio).
Y
- durante los 3 meses consecutivos previos al inicio del tratamiento profiláctico IV con CINRYZE, tener antecedente de al menos 2,0 crisis de AEH moderadas1 o intensas2 al mes (en promedio).
4. Si no están recibiendo tratamiento profiláctico intravenoso con CINRYZE, tener antecedentes de al menos 2,0 crisis de AEH moderadas o intensas al mes (en promedio) durante los 3 meses consecutivos previos a la aleatorización.
5. Comprometerse a evitar en lo posible sus desencadenantes conocidos de AEH durante el estudio.
6. Comprometerse a cumplir el calendario de valoraciones y procedimientos definido en el protocolo.
7. Si son mujeres, ser posmenopáusicas (sin menstruación durante 1 año o más), estar esterilizadas quirúrgicamente o seguir un método anticonceptivo no hormonal aceptable, como un dispositivo intrauterino o método de barrera, durante al menos un ciclo menstrual completo antes de la visita de selección y comprometerse a seguir utilizándolo hasta 30 días después del tratamiento, o haber empleado productos anticonceptivos hormonales durante al menos 3 meses antes de la primera dosis del fármaco del estudio en el periodo de tratamiento 1 y comprometerse a seguir utilizándolos hasta 30 días después del tratamiento.
8. Si son varones, estar esterilizados quirúrgicamente o comprometerse a seguir un método anticonceptivo aceptable (p. ej., de barrera) desde la visita de selección hasta 2 meses después de la última dosis del fármaco del estudio.
9. Si son adultos (>= 18 años), estar informados de la naturaleza del estudio y dar su consentimiento informado por escrito antes de que se realice cualquier procedimiento específico del estudio.
O
Si son niños (<18 años), que un padre o tutor legal que esté informado de la naturaleza del estudio dé el consentimiento informado por escrito para que el niño participe en el estudio antes de que se realice cualquier procedimiento específico del estudio (con asentimiento del niño cuando proceda). Por otro lado, algunos centros u ORI pueden permitir que se informe a adolescentes de <18 años de edad de la naturaleza del estudio y den su consentimiento informado por escrito sin el consentimiento de un padre o tutor legal.

E.4

Principal exclusion criteria

To be eligible for this protocol, a subject must not:
Have received any C1 INH therapy or any blood products for treatment or prevention of an HAE attack within 7 days prior to the first dose of study drug in Treatment Period 1.
Be receiving prophylactic IV CINRYZE that exceeds the approved dosing regimen of 1000 U every 3 or 4 days (maximum weekly dose of 2000 U).
Have had HAE attack signs or symptoms within 2 days prior to the first dose of study drug in Treatment Period 1.
Have any change (start, stop, or change in dose) in androgen therapy (e.g., danazol, oxandrolone, stanozolol, testosterone) within 14 days prior to the first dose of study drug in Treatment Period 1.
If female, have started taking or changed the dose of any hormonal contraceptive regimen or hormone replacement therapy (i.e., estrogen/progestin containing products) within 3 months prior to the first dose of study drug in Treatment Period 1.
Have a history of hypercoagulability (abnormal blood clotting).
Have a history of allergic reaction to C1 INH products, including CINRYZE (or any components of CINRYZE), or other blood products.
Have a known allergy to hyaluronidase or any other ingredient in the study formulation.
Be pregnant or breastfeeding.
Have received an investigational study drug within 30 days prior to the first dose of study drug in Treatment Period 1.
Have, as determined by the Investigator and/or the Sponsor?s medical monitor, any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results.

Para poder participar en este protocolo, los sujetos no deberán:
1. Haber recibido cualquier tratamiento con INH C1 o hemoderivados para el tratamiento o la prevención de una crisis de AH en los 7 días previos a la primera dosis del fármaco del estudio en el periodo de tratamiento 1.
2. Estar recibiendo CINRYZE IV profiláctico en cantidad superior a la pauta posológica aprobada de 1000 U cada 3 ó 4 días (dosis semanal máxima de 2000 U).
3. Haber tenido signos o síntomas de crisis de AEH en los 2 días previos a la primera dosis del fármaco del estudio en el periodo de tratamiento 1.
4. Presentar cualquier cambio (inicio, interrupción o cambio de dosis) de un tratamiento con andrógenos (p. ej., danazol, oxandrolona, estanozolol, testosterona) en los 14 días previos a la primera dosis del fármaco del estudio en el periodo de tratamiento 1.
5. Si son mujeres, haber empezado a tomar o cambiado la dosis de cualquier régimen anticonceptivo hormonal o tratamiento hormonal sustitutivo (es decir, productos que contengan estrógenos/progestágeno) en los 3 meses previos a la primera dosis del fármaco del estudio en el periodo de tratamiento 1.
6. Tener antecedentes de hipercoagulabilidad (coagulación anormal de la sangre).
7. Tener antecedentes de reacción alérgica a productos con INH C1, incluido CINRYZE (o a cualquier componente de CINRYZE), u otros hemoderivados.
8. Tener alergia conocida a la hialuronidasa o a cualquier otro componente de la formulación en estudio.
9. Estar embarazadas o practicar la lactancia materna.
10. Haber recibido un fármaco en investigación en los 30 días previos a la primera dosis del fármaco del estudio en el periodo de tratamiento 1.
11. Tener, según lo determinado por el investigador o el monitor médico del promotor, cualquier proceso quirúrgico o médico que pueda interferir en la administración del fármaco del estudio o en la interpretación de los resultados del estudio.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the number of angioedema attacks recorded during each treatment period, normalized for the number of days the subject participated in that period.

El criterio principal de valoración de la eficacia es el número de crisis de angioedema registradas durante cada periodo de tratamiento, normalizada para el número de días que el sujeto participó en ese período.

E.5.1.1

Timepoint(s) of evaluation of this end point

End of the treatment period.

Final del periodo de tratamiento.

E.5.2

Secondary end point(s)

Response status (i.e., Responder/Non-Responder) during each active treatment period. This endpoint is exploratory in that several definitions of response will be evaluated. These definitions will incorporate attributes of a subject?s HAE attacks including:
- Changes in attack rates (either absolute or relative).
- Anatomic location.
- Severity of pain as measured by a VAS.
- Duration (in days).
Time (measured in days from the first dose of study drug in a treatment period) to the first HAE attack during each treatment period.

El estado de respuesta (es decir, con/sin respuesta) durante cada período de tratamiento activo. Este criterio de valoración es exploratorio, ya que se evaluarán varias definiciones de respuesta. Estas definiciones incorporarán características de las crisis de AEH de un sujeto como:
- Los cambios de las tasas de crisis (absolutos o relativos).
- La localización anatómica.
- La intensidad del dolor medida mediante una EAV.
- La duración (en días).
- El tiempo (medido en días desde la primera dosis del fármaco del estudio en un período de tratamiento) hasta la primera crisis de AEH durante cada período de tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

End of the treatment period.

Final del periodo de tratamiento.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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

Yes

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

E.8.1.6

Cross over

Yes

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

dosis diferentes del mismo producto.

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

Last visit last subject.

Última visita del último 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

Yes

F.1.1