Clinical Trials Register

Summary
EudraCT Number:	2015-000188-15
Sponsor's Protocol Code Number:	AL1402ac
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:	2016-12-09
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

2015-000188-15

A.3

Full title of the trial

A multicenter randomized double-blind adaptive placebo-controlled clinical trial for evaluation of efficacy and safety of specific immunotherapy with an aluminium hydroxide-adsorbed allergoid preparation of house dust mite
(Dermatophagoides pteronyssinus) in patients with allergic bronchial asthma and with allergic rhinitis or rhinoconjunctivitis

Estudio multicéntrico, aleatorio, doble ciego adaptativo, controlado con placebo para la evaluación de la eficacia y la seguridad de inmunoterapia especifica con una preparación alergoide de ácaros de polvo doméstico (Dermatophagoides Pteronyssinus) adheridas sobre hidróxido de aluminio en pacientes con asma bronquial alérgico y rinitis alérgica o rino-conjuntivitis

A.3.1

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

Phase III trial of specific immunotherapy with allergoid preparation of house dust mite in patients with allergic bronchial asthma and with allergic rhinitis or rhinoconjunctivitis

Ensayo fase III de inmunoterapia específica con una preparación alergoide de ácaros de polvo doméstico en pacientes con asma bronquial alérgico y rinitis alérgica o rino-conjuntivitis

A.4.1

Sponsor's protocol code number

AL1402ac

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/286/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Allergopharma GmbH & Co. KG
B.1.3.4	Country	Germany
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	Allergopharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Allergopharma GmbH & Co. KG
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Hermann-Körner-Straße 52
B.5.3.2	Town/ city	Reinbek
B.5.3.3	Post code	21465
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4940 727 65 - 0
B.5.5	Fax number	+4940 727 65 – 600
B.5.6	E-mail	AL1402ac@allergopharma.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.3.1	Product name	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension 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	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
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)	Yes
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension 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	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
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	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)	Yes
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension 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	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5000
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)	Yes
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: 4
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.3.1	Product name	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.4	Pharmaceutical form	Suspension 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	N/A
D.3.9.1	CAS number	N/A
D.3.9.2	Current sponsor code	House dust mite allergoid (Dermatophagoides pteronyssinus)
D.3.9.3	Other descriptive name	DERMATOPHAGOIDES PTERONYSSINUS
D.3.9.4	EV Substance Code	SUB25740
D.3.10	Strength
D.3.10.1	Concentration unit	PNU/ml protein nitrogen units/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	9000
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)	Yes
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	Suspension for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

allergic bronchial asthma and allergic rhinitis or rhinoconjunctivitis

asma bronquial alérgico y rinitis alérgica o rino-conjuntivitis

E.1.1.1

Medical condition in easily understood language

asthma with symptoms of rhinitis or rhinoconjunctivitis caused by house dust mite allergens

Asma con síntomas de rinitis o rinoconjuntivitis, desencadenado por alérgenos de ácaros del polvo doméstico.

E.1.1.2

Therapeutic area

Body processes [G] - Immune system processes [G12]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10039097
E.1.2	Term	Rhinoconjunctivitis
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10001705
E.1.2	Term	Allergic asthma
E.1.2	System Organ Class	100000004855

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10001723
E.1.2	Term	Allergic rhinitis
E.1.2	System Organ Class	100000004855

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 aim of this clinical trial is to demonstrate efficacy and to evaluate safety of AIT with an aluminium hydroxide adsorbed allergoid preparation of major allergens of D p in patients with allergic bronchial asthma (acc. to GINA 2015) and allergic rhinitis or rhinoconjunctivitis caused by house dust mites.

El propósito de este ensayo clínico es demostrar la eficacia y evaluar la seguridad de Inmunoterapia con antígenos (IA) con una preparación alergoide adsorbida a hidróxido de aluminio de los principales alérgenos de D p en pacientes con asma bronquial alérgico (según criterios GINA 2015) y rinitis alérgica o rinoconjuntivitis causado por ácaros del polvo doméstico.

E.2.2

Secondary objectives of the trial

None

Ninguno

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent and assent according to local requirements before any trial-related activities started (a trial-related activity is any procedure that would not have been performed during the routine management of the patient.)
2. Male or female outpatient between 12 and 65 years (both inclusive)
3. IgE-mediated allergic bronchial asthma treated according GINA step 2-4 with rhinitis or rhinoconjunctivitis induced by house dust mite documented by
• SPT wheal for D p ≥ 3 mm in diameter
• histamine (0.1% histamine) wheal ≥ 3 mm
• a negative control reaction (NaCl) wheal < 2 mm
• Immunoassay result specific IgE > 1.5 kU/L to D p
• symptoms of asthma and rhinitis or rhinoconjunctivitis e.g. during the months September to February or over the entire year
4. confirmed diagnosis of asthma
• treatment according to GINA 2015 during the last year as documented by requirement of ICS and requirement of a bronchodilator
• FEV1 increase of ≥ 12% and 200 mL of the baseline FEV1 after inhalation of 400µg of Salbutamol or other short acting bronchodilator equivalent (historical data not older than 2 years are acceptable)
• Achievement of asthma control criteria (ACQ6 ≤ 1.0 scores in 2 consecutive weeks at the end of the assessment period) during the baseline diary phase within a required ICS dose between 400 to 1200 µg Budesonide per day

1.Consentimiento informado por escrito y consentimiento según los requisitos locales antes de que comience cualquier actividad relacionada con el ensayo (una actividad relacionada con el ensayo es cualquier procedimiento que no se hubiera realizado durante el tratamiento habitual del paciente)
2.Pacientes, hombres o mujeres, de entre 12 y 65 años (ambos incluidos)
3.Asma bronquial alérgico mediado por IgE según criterios GINA 2-4 con rinitis o rinoconjuntivitis inducido por ácaros de polvo doméstico documentado por
•PPC (prueba de puncíón cutánea) habón para D p ≥ 3 mm en diámetro
•Habón para histamina (histamina 0.1%) ≥ 3 mm
•Un habón de reacción control negativa (NaCl) < 2 mm
•Resultado de inmunoensayo IgE específico > 1.5 kU/L a D p
•Síntomas de asma y rhinitis o rinoconjuntivitis p.e. durante los mese de Septiembre a Febrero o a lo largo de todo el año
4. Diagnóstico confirmado de asma (sección 6.2.3.3.)
•Tratamiento según GINA 2015 durante el último año documentado por el requerimiento de CEI y requerimiento de broncodilatador
•Aumento del valor FEV1 ≥ 12% y 20mL del valor basal de FEV1 tras la inhalación de 400µg de Salbutamol u otro broncodilatador de acción rápida similar (datos históricos de no más de 2 años son aceptables)
•El logro de los criterios de control del asma (puntuación ≤ 1.0 en cuestionario ACQ6 en 2 semanas consecutivas al final del periodo de evaluación) durante la fase basal de registro en diario con la dosis de CEI requerida entre 400 y 1200 µgde Budesonida por día

E.4

Principal exclusion criteria

General criteria:
1. Unable to understand and comply with the requirements of the trial, as judged by the investigator
2. Currently participating in any other trial or in participating in any other trial within 30 days before inclusion in this trial
3. Low compliance, persistent incorrect inhaler technique as assessed by the investigator or inability to understand instructions or trial documents
4. Involved in the planning and conduct of the trial
5. Employee of Allergopharma GmbH & Co. KG or of one of the trial sites
6. Any relationship of dependence with the sponsor or with the investigator
7. Previously enrolled or randomized to treatment in the present trial
8. Mentally disabled
9. Institutionalized due to an official or judicial order
For females with childbearing potential (i.e. females who are not chemically or surgically sterilized or females who are not post-menopausal):
10. Positive pregnancy test
11. Use of an unacceptable or unreliable contraceptive method during the trial, as judged by the investigator (reliable and highly effective methods of birth control defined as failure rate less than 1% per year)
12. Pregnant, breast feeding or wishes to breast feed
13. Seeking to become pregnant during the course of the trial
Immunotherapy criteria:
14. Any AIT with house dust mites
15. Current treatment with any kind of immunotherapy
16. Any AIT with unknown allergen
17. Clinically relevant symptoms to other regional specific allergens which interfere with the assessment period of October to January. Exceptions are symptoms to allergens of cat and dog, if the patient has no direct contact to these animals.
18. Sensitization in the immunoassay ≥ 0.7 kU/L against region specific allergens which interfere with the assessment period of October to January. Exceptions are sensitizations to storage mites if the sensitization assessed by immunoassay is lower than the sensitization to at least one of the house dust mites (D p or D f). Exceptions are sensitizations assessed by immunoassay to cat and dog, if the patient has no direct contact to these animals.
Diseases and health status:
19. Clinically relevant rhinitis or respiratory symptoms related to other reasons (e.g. chronic sinusitis, COPD)
20. FEV1 < 70% of predicted normal (ECSC)[17]
21. Asthma or rhinitis symptoms for 20 years or longer
And the usual exclusion criteria for immunotherapy regarding health status and medical requirement.

Criterios Generales:
1.Incapacidad de entender y cumplir con los requerimientos del ensayo, a juicio del investigador
2.Actualmente participación en otro ensayo clínico o participación en otro ensayo clínico en los 30 días previos a la inclusión en este ensayo
3.Bajo cumplimiento, incorrecta técnica de inhalación persistente según lo evaluado por el investigador o incapacidad para comprender las instrucciones o documentos del ensayo
4.Involucrado en la planificación y desarrollo del ensayo
5.Empeados de Allergopharma GmbH & Co. KG o de cualquiera de los centros participantes en el ensayo
6.Cualquier relación de dependencia con el Promotor o con el Investigador
7.Previamente incluido o aleatorizado a tratamiento en el ensayo actual
8.Personas con discapacidad mental
9.Institucionalización debida a una orden oficial o judicial
Para mujeres en edad fértil, (p.e. mujeres no esterilizadas química o quirúrgicamente o mujeres que no sean post-menopaúsicas):
10.Test de embarazo positivo
11.Uso de un método anticonceptivo inaceptable o poco fiable durante el ensayo, según la opinión del investigador (métodos fiables y altamente eficaces de control de la natalidad definidos como aquellos con una tasa de fracaso inferior al 1% al año)
12.Embarazadas, en period de lactancia o con deseos de lactancia
13.Tratando de quedar embarazadas durante la duración del ensayo
Criterios de inmunoterapia:
14.Cualquier IA con ácaros de polvo doméstico
15.Tratamiento actual con cualquier tipo de inmunoterapia
16.Cualquier IA con alérgenos desconocidos
17.Síntomas clínicamente relevantes a otros alérgenos regionales específicos que interfieran en el periodo de evaluación entre Octubre y Enero. Excepto los síntomas a alérgenos de gatos y perros si el paciente no tiene contacto directo con estos animales.
18.Sensibilización en inmunoensayo ≥ 0,7 kU/L frente a alérgenos específicos de la región que interfieren con el período de evaluación entre Octubre y Enero. Excepto sensibilizaciones a los ácaros de almacén, si la sensibilización evaluada por inmunoensayo es más baja que la sensibilización a al menos uno de los ácaros del polvo doméstico (D p o D f). Excepto sensibilizaciones evaluadas por inmunoensayo a gato y perro, si el paciente no tiene contacto directo con estos animales
Enfermedades y estado de salud:
19.Síntomas clínicamente relevantes de rinitis o respiratorios relacionados con otras causas (p.e. sinusitis crónica, EPOC)
20.FEV1 < 70% del valor normal previsto (ECSC)[17]
21.Síntomas de asma o rinitis durante 20 años o más
22.Valores de laboratorio superiores a Grado 1 según la guía de la FDA para industria (Escala de Calificación de toxicidad para adultos sanos y adolescentes voluntarios inscritos en los ensayos clínicos de vacunas preventivas). Para la evaluación aplicarán los rangos normales del laboratorio central.
23.Enfermedades agudas o crónicas graves (p.e. diabetes mellitus tipo I, neoplasia maligna, insuficiencia renal crónica, enfermedad de reflujo gastro-esofágico, IMC> 30, el asma inducida por aspirina), enfermedades inflamatorias graves (hígado, riñones)
24.Enfermedades autoinmunes, defectos inmunitarios que incluyen supresión inmunitaria, inmunopatías inducidas por el complejo inmune(p.e. VIH, pacientes post- trasplantados, lupus eritematoso, enfermedad de Grave)
25.Trastornos psiquiátricos y psicológicos severos entre ellos el deterioro de la cooperación (por ejemplo, el abuso de alcohol o drogas)
26.Fumadores
27.Ex-fumadores de 10 paquetes/año o más (un paquete/año se define como 20 cigarrillos al día durante un año)
28.Convulsiones recurrentes
29.Alteraciones secundarias irreversibles del órgano reactivo (p.e. enfisema, bronquiectasias etc.)
Medicaciones:
30.Tratamiento con beta-bloqueantes (local o sistémico)
31.Contraindicación para el uso de adrenalina (p.e. enfermedad sintomática aguda o crónica cardíaca coronaria, hipertensión grave)
32.En tratamiento o que hayan completado tratamiento con anticuerpos anti-IgE
33.En tratamiento a largo plazo o que hayan completado tratamiento con tranquilizantes u otras drogas psicoactivas
34.Asma controlado en periodo basal tras dos pasos de reducción de CEI

E.5 End points

E.5.1

Primary end point(s)

This is a confirmatory phase III pivotal study. The primary endpoint is the change in dose steps of the minimum daily ICS dose required to ensure asthma control according to the ACQ6 (ACQ6 score ≤ 1.0) between baseline and after AIT. The ICS dose will be determined by means of diary entries as described in Section 5.1.

Este es un estudio pivotal de fase III confirmatorio. El objetivo primario es el cambio de dosis de la dosis mínima de CEI requerida para asegurar el control del asma evaluado por el cuestionario ACQ6 (puntuación ACQ6≤ 1.0) entre el periodo basal y tras la IA.

E.5.1.1

Timepoint(s) of evaluation of this end point

after the end of the trial

después del final del ensayo

E.5.2

Secondary end point(s)

The following secondary endpoints will be assessed:
Efficacy
“Change” refers to the change between the baseline value and the value after AIT.
• Response status in terms of improvement by at least one dose step of the minimum daily ICS dose required to ensure asthma control between baseline and after AIT
• Response status in terms of no need for ICS after AIT
• Change of the minimum daily ICS dose (Budesonide) in µg required to ensure asthma control.
• Change in ACQ6 score under the highest daily ICS dose the patient was not controlled at baseline according to the ACQ6.
• Change in severity of asthma symptoms with the highest daily ICS dose the patient was not controlled at baseline
• Change in use of bronchodilator rescue medication (Salbutamol) with the daily ICS highest dose the patient was not controlled at baseline
• Change in pre-bronchodilator morning peak flow with the highest daily ICS dose the patient was not controlled at baseline
• Change in the number of night time awakening with the highest daily ICS dose the patient was not controlled at baseline
• Change in limitation of daily activities with the highest daily ICS dose the patient was not controlled at baseline
• Change in the number of symptom free days with the highest daily ICS dose the patient was not controlled at baseline
• Change in the outcome of the Quality of Life Questionnaire (Mini-AQLQ) with the highest daily ICS dose the patient was not controlled at baseline
• Change in patient’s FEV1 value with the highest daily dose ICS the patient was not controlled at baseline
• Change of the Combined Symptom (rhinitis symptoms) and Medication Score (CSMS) under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of the Combined Symptom (rhinitis- and conjunctivitis symptoms) and Medication Score (CSMS) under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of rhinitis symptoms of the CSMS under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of the rhinitis medication score of the CSMS under the lowest daily ICS dose required to ensure asthma control at baseline
• Change of IgG4
• Change of eosinophils
• The time until the first moderate or severe asthma exacerbation during the diary phase after AIT
• The time until the first moderate or severe asthma exacerbation from the time of first injection until the end of trial.
• The number of asthma exacerbations (moderate or severe) during the diary phase after AIT.
• The number of asthma exacerbations (moderate or severe) from the time of first injection until the end of trial.
• Number of severe asthma exacerbations during the diary phase after AIT
The number of severe asthma exacerbations from the time of first injection until the end of trial.
• Number of moderate asthma exacerbations during the diary phase after AIT
• The number of moderate asthma exacerbations from the time of first injection until the end of trial.
Safety
In addition to the efficacy endpoints, the safety of the treatment during the entire trial period will be assessed by
• Adverse events
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)
• Vital signs (resting blood pressure, pulse rate, and respiratory rate)
• An assessment of the overall tolerability by the investigator and the patient using a 5 point Likert scale (Likert, 1932)

Se evaluarán los siguientes objetivos secundarios:
Eficacia
“Cambio” se refiere al cambio entre el valor basar y el valor tras la IA.
•Estado de respuesta en términos de mejora por al menos un cambio de dosis de la dosis mínima de CEI requerida para asegurar el control del asma entre el perido basal y después de la IA
•Estado de respuesta en términos de no necesitar CEI tras la IA
•Cambio en la dosis mínima de CEI (Budesonida) en µg requerida para asegurar control del asma
•Cambio en la puntuación ACQ6 por debajo de la dosis más alta de CEI en la que el paciente no estaba controlado en el periodo basal de acuerdo al cuestionario ACQ6
•Cambio en la gravedad de los síntomas de asma con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en el uso de medicación de rescate broncodilatadora (Salbutamol) con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en el flujo máximo por la mañana pre-broncodilatador con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en el número de veces que se despierta por la noche con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en la limitación para realizar las actividades diarias con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en el número de días libres de síntomas con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en el resultado del cuestionario de calidad de vida (Mini-AQLQ) con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambios en el valor FEV1 del paciente con la dosis diaria de CEI más alta en la que el paciente no estaba controlado en el periodo basal
•Cambio en la puntuación de síntomas combinados (síntomas de rinitis) y medicación (CSMS) con la dosis más baja de CEI requerida para el control de asma en el periodo basal
•Cambio en la puntuación de síntomas combinados (síntomas de rinitis y conjuntivitis) y medicación (CSMS) con la dosis más baja de CEI requerida para el control de asma en el periodo basal
•Cambio de los síntomas de rinitis del CSMS bajo la dosis más baja de CEI requerida para el control de asma en el periodo basal
•Cambio en la puntuación de medicación de rinitis del CSMS bajo la dosis más baja de CEI requerida para el control de asma en el periodo basal
•Cambio en IgG4
•Cambio en eosinófilos
•El tiempo hasta la primera exacerbación moderada o grave del asma durante la fase de diario después de la IA
•El tiempo hasta la primera exacerbación moderada o grave del asma desde el momento de la primera inyección hasta el final del ensayo
•El número de exacerbaciones del asma (moderada o grave) durante la fase de diario después de la IA
•El número de exacerbaciones del asma (moderada o grave) desde el momento de la primera inyección hasta el final del ensayo
•El número de exacerbaciones graves de asma durante la fase de diario después de la IA.
El número de exacerbaciones graves de asma desde el momento de la primera inyección hasta el final del ensayo.
•El número de exacerbaciones moderadas de asma durante la fase de diario después de la IA
•El número de exacerbaciones moderadas de asma desde el momento de la primera inyección hasta el final del ensayo.

Seguridad
Además de los objetivos de eficacia, se evaluará la seguridad del tratamiento durante todo el período de prueba por:
•Efectos adversos
•Pruebas de laboratorio clínico (hematología, bioquímica clínica, y urianálisis)
•Signos vitales (presión sanguínea tumbado, pulso y frecuencia respiratoria)
•Una evaluación por parte del investigador y del paciente de la tolerabilidad global utilizando una escala Likert de 5 puntos (Likert, 1932)

E.5.2.1

Timepoint(s) of evaluation of this end point

After the end of the trial

Después del final del ensayo

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

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)

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

Canada

Russian Federation

Serbia

Ukraine

E.8.7

Trial has a data monitoring committee

Yes

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

The end of the trial is defined as the date of last database lock in order to permit data cleaning after the last patient visit.

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

Number of subjects for this age range:

133

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

133

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

311

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

165

F.4.2

For a multinational trial

F.4.2.1

In the EEA

315

F.4.2.2

In the whole clinical trial

444

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)

Standard of medical care

Práctica médica habitual

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

2016-12-23

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-06-25

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