E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with moderate to severe seasonal rhinitis or rhinoconjunctivitis with or without asthma |
Pacientes con rinitis estacional o rinoconjuntivitis con o sin asma |
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E.1.1.1 | Medical condition in easily understood language |
Patients suffering from hay fever with or without asthma |
Pacientes que padecen alergia al polen con o sin asma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039776 |
E.1.2 | Term | Seasonal allergic rhinitis |
E.1.2 | System Organ Class | 100000023864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001726 |
E.1.2 | Term | Allergic rhinitis due to pollen |
E.1.2 | System Organ Class | 100000023864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001728 |
E.1.2 | Term | Allergic rhinoconjunctivitis |
E.1.2 | System Organ Class | 100000014962 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001705 |
E.1.2 | Term | Allergic asthma |
E.1.2 | System Organ Class | 100000015470 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001723 |
E.1.2 | Term | Allergic rhinitis |
E.1.2 | System Organ Class | 100000016169 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main objective of this therapeutic phase II trial is to evaluate the safety and tolerability of an accelerated high dose escalation schedule with one strength for allergen immunotherapy with Allergovit® 6-Grasses compared to the standard escalation schedule with two strengths. Pediatric, adolescent and adult patients with rhinitis or rhinoconjunctivitis caused by grass pollen, with or without allergic asthma on a well controlled level, will be enrolled. |
El objetivo principal de este estudio terapéutico de fase II es comparar la seguridad y tolerabilidad de una pauta posológica de incremento acelerado a dosis altas con una concentración de inmunoterapia con alérgenos con Allergovit® 6 gramíneas con la pauta posológica de incremento estándar con dos concentraciones. Se incluirán al estudio pacientes pediátricos, adolescentes y adultos con rinitis o rinoconjuntivitis provocada por polen de gramíneas, con o sin asma alérgica a un nivel bien controlado |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
No apliable |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent given from patient and if applicable parents/legal guardian(s) 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. Legally competent male or female outpatient 3. Age between 5 to ≤ 65 years 4. IgE-mediated seasonal allergic rhinitis or rhinoconjunctivitis with or without allergic asthma caused by grass pollen documented by: • Skin prick test (SPT): • wheal for grass pollen ≥ 3 mm in diameter • Histamine wheal ≥ 3 mm (positive control) • NaCl reaction < 2 mm (negative control) • Immunoassay result for specific IgE ≥ 0.70 kU/L to grass pollen 5. At least 1 month symptoms of allergic rhinitis or rhinoconjunctivitis in May to August triggered by grass pollen exposure over the last two seasons. 6. In case of bronchial asthma at entry: confirmed diagnosis of asthma according to GINA guideline (GINA, 2017) 7. In case of a diagnosed asthma: asthma symptoms classified as being “well controlled” according to GINA guideline (GINA, 2017) 8. Previous treatment with anti-allergic treatment for at least 2 seasons prior to enrolment |
1.Consentimiento informado por escrito del paciente y, si procede, de los padres o tutores legales, de acuerdo con los requisitos locales, antes de iniciar cualquier actividad relacionada con el estudio (una actividad relacionada con el estudio es todo procedimiento que no se hubiese realizado durante el tratamiento convencional del paciente) 2.Paciente ambulatorio varón o mujer con capacidad jurídica 3.Edad entre 5 y ≤ 65 años 4.Rinitis o rinoconjuntivitis estacional mediada por IgE, con o sin asma alérgica, provocada por polen de gramíneas documentada por medio de: •Prueba cutánea por punción (PCP): •Roncha para polen de gramíneas ≥ 3 mm de diámetro •Roncha de histamina ≥ 3 mm (control positivo) •Reacción al NaCl < 2 mm (control negativo) •Inmunoanálisis para IgE específica ≥ 0,70 kU/l a polen de gramíneas 5.Al menos 1 mes de síntomas de rinitis o rinoconjuntivitis alérgica entre mayo y agosto, desencadenados por la exposición al polen de gramíneas durante las dos últimas estaciones. 6.En caso de asma bronquial en el momento de entrar en el estudio: diagnóstico confirmado de asma de acuerdo con las directrices de la GINA (GINA, 2017) 7.En caso de asma diagnosticada: síntomas de asma clasificados como "bien controlados" de acuerdo con las directrices de la GINA (GINA, 2017) 8.Tratamiento anterior con antialérgicos como mínimo 2 estaciones antes de la inclusión |
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E.4 | Principal exclusion criteria |
General criteria: 1. Patient or parents/legal guardian(s) is unable to understand and comply with the requirements of the trial, as judged by the investigator 2. Currently participating in any other clinical trial or participating in any other clinical trial within 30 days prior informed consent for this trial 3. Low compliance or inability to understand instructions/trial documents 4. Involvement 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. Previous randomization 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 or pregnant 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. Wish to breast feed or breast feeding 13. Wish to become pregnant during the course of the trial Immunotherapy criteria: 14. History of a confirmed anaphylaxis after an AIT injection 15. AIT with grass pollen within the last 5 years 16. Current treatment with any kind of immunotherapy 17. AIT with unknown allergen within the last 5 years Diseases and health status: 18. Clinically relevant chronic rhinoconjunctival or respiratory symptoms related to other reasons than allergy 19. Forced expiratory volume in 1 second (FEV1) < 70 % of predicted normal values (ECSC) under adequate asthma treatment according to GINA guidelines (GINA, 2017) 20. Uncontrolled or partly controlled asthma according to GINA guidelines (GINA, 2017) 21. Acute asthma attack within the last 6 months prior to randomization defined as unscheduled doctors visit, hospitalization, or emergency visit 22. For adult patients, rhinoconjunctival atopic symptoms for 20 years or longer 23. Severe acute or chronic diseases (e.g. chronic urticaria, mastocytose, active tuberculosis, diabetes mellitus type I, malignant neoplasia, chronic renal failure), severe inflammatory diseases (liver, kidneys) 24. Autoimmune diseases, immune defects including immunosuppression, immune-complex-induced immunopathies (e.g. HIV, post-transplant patients, lupus erythematodes [SLE], vitiligo, Grave’s disease, multiple sclerosis) 25. Severe psychiatric and psychological disorders including impairment of cooperation (e.g. alcohol or drug abuse) 26. Recurrent seizures (e.g. febrile convulsion, untreated epileptisia) 27. Irreversible secondary alterations of the reactive organ (e.g. emphysema, bronchiectasis) 28. Laboratory values greater than grade 1 according to the FDA Guidance for Industry (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials). For assessment the normal ranges of the central laboratory should be applied. Medications: 29. Use of beta-blockers (locally or systemically), ACE inhibitors 30. Contraindication for use of adrenalin (e.g. acute or chronic symptomatic coronary heart disease, severe hypertension) 31. Completion or ongoing treatment with anti-IgE-antibody 32. Completion or ongoing long-term treatment with tranquilizer or other psychoactive drugs |
Criterios generales: 1.En opinión del investigador, el paciente o los padres o tutores legales son incapaces de entender y cumplir los requisitos del estudio 2.Participación actual en otro estudio clínico o participación en cualquier otro estudio clínico en los 30 días previos al consentimiento informado de este estudio 3.Es caso bajo cumplimiento o incapacidad de entender las instrucciones o la documentación del estudio 4.Implicación en la planificación y realización del estudio 5.Empleado de Allergopharma GmbH & Co. KG o de uno de los centros de estudio 6.Cualquier relación de dependencia con el promotor o investigador 7.Aleatorización anterior al tratamiento en el estudio actual 8.Discapacidad mental 9.Internamiento debido a una orden oficial o judicial Para mujeres en edad fértil (es decir, mujeres no esterilizadas químicamente ni quirúrgicamente o mujeres no posmenopáusicas): 10.Prueba de embarazo positiva o embarazada 11.Utilización de un método anticonceptivo inaceptable o de poca confianza durante el estudio, en opinión del investigador (los métodos anticonceptivos fiables y altamente eficaces tienen una tasa de fallo inferior al 1 % anual) 12.Deseo de dar el pecho o en lactancia 13.Deseo de quedarse embarazada durante la realización del estudio Criterios inmunoterapéuticos: 14.Antecedentes de anafilaxia confirmada tras una inyección de inmunoterapia con alérgenos (AIT) 15.AIT con polen de gramíneas en los últimos 5 años 16.Tratamiento actual con cualquier tipo de inmunoterapia 17.AIT con un alérgeno desconocido en los últimos 5 años Enfermedades y estado de salud: 18.Síntomas rinoconjuntivales o respiratorios crónicos clínicamente relevantes por causas distintas a la alergia 19.Volumen espiratorio forzado en un segundo (FEV1) < 70 % de los valores normales predichos (ECSC) con un tratamiento adecuado del asma de acuerdo con las directrices de la GINA (GINA, 2017) 20.Asma no controlada o parcialmente controlada de acuerdo con las directrices de la GINA (GINA, 2017) 21.Crisis asmática aguda en los 6 meses previos a la aleatorización, definida como visita no programada al médico, hospitalización o visita de emergencia 22.En pacientes adultos, síntomas rinoconjuntivales atópicos durante 20 años o más 23.Enfermedades agudas o crónicas graves (p. ej., urticaria crónica, mastocitosis, tuberculosis activa, diabetes mellitus tipo I, neoplasia maligna, insuficiencia renal crónica), enfermedades inflamatorias graves (hígado, riñones) 24.Enfermedades autoinmunes, defectos inmunológicos incluidos inmunosupresión, inmunopatías inducidas por inmunocomplejos (p. ej., VIH, pacientes postrasplante, lupus eritematoso [LES], vitiligo, enfermedad de Graves, esclerosis múltiple) 25.Trastornos psiquiátricos y psicológicos graves con alteración de la cooperación (p. ej., alcoholismo o drogadicción) 26.Convulsiones recurrentes (p. ej., convulsión febril, epilepsia sin tratar) 27.Alteraciones secundarias irreversibles del órgano reactivo (p. ej., enfisema, bronquiectasias) 28.Valores de laboratorio superiores al grado 1 de acuerdo con la Guidance for Industry (Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials) de la FDA. En la evaluación se deberán aplicar los intervalos normales del laboratorio central. Medicamentos: 29.Uso de betabloqueantes (locales o sistémicos), inhibidores de la ECA 30.Contraindicaciones para el uso de adrenalina (p. ej., cardiopatía coronaria sintomática aguda o crónica, hipertensión grave) 31.Finalización del tratamiento o tratamiento en curso con anticuerpos anti IgE 32.Finalización del tratamiento o tratamiento a largo plazo en curso con tranquilizantes u otros fármacos psicoactivos |
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E.5 End points |
E.5.1 | Primary end point(s) |
The aim of the trial is to obtain information about the safety and tolerability of an accelerated dose escalation schedule with one strength for allergen immunotherapy with Allergovit® 6-Grasses. The following descriptive safety variables will be considered: • Number, incidence, time of onset, type and intensity of AEs and serious adverse events (SAE) according to MedDRA primary system organ class (SOC) and preferred term • Number, incidence, time of onset, type and intensity of AEs and serious adverse events assessed as drug related (by investigator) according to MedDRA primary system organ class (SOC) and preferred term • Incidence and intensity of allergic systemic reactions after injections according to the World Allergy Organization (WAO) grading system (see Section 18.4) • Number of patients reaching the maintenance dose without dose adjustment due to adverse events • Change of laboratory values (hematology, clinical chemistry and urinalysis) measured before and after the treatment phase • Change of vital signs and lung function measured before and after the treatment phase • Assessment of the overall tolerability by the investigator and the patient using a 5 point Likert scale (Likert, 1932) |
El objetivo del estudio es obtener información sobre la seguridad y tolerabilidad de una pauta posológica de incremento acelerado de la dosis con una concentración de inmunoterapia con alergógenos con Allergovit® 6 gramíneas. Se tendrán en cuenta las siguientes variables de seguridad descriptivas: •Número, incidencia, momento de aparición, tipo e intensidad de los AE y acontecimientos adversos graves (AAG) de acuerdo con la clasificación primaria de órganos y sistemas (SOC) y el término preferente MedDRA •Número, incidencia, momento de aparición, tipo e intensidad de los AE y acontecimientos adversos graves calificados como relacionados con el fármaco (por el investigador) de acuerdo con la clasificación primaria de órganos y sistemas (SOC) y el término preferente MedDRA •Incidencia e intensidad de las reacciones alérgicas sistémicas tras las inyecciones, de acuerdo con el sistema de clasificación de la Organización Mundial de Alergia (WAO) (ver sección 18.4) •Número de pacientes que llegan a la dosis de mantenimiento sin ajustes de la dosis debido a acontecimientos adversos •Cambio de los valores de laboratorio (hematología, bioquímica clínica y análisis de orina) detectado antes y después de la fase de tratamiento •Cambio de los signos vitales y de la función pulmonar detectado antes y después de la fase de tratamiento •Evaluación de la tolerabilidad global por el investigador y el paciente mediante una escala de Likert de 5 puntos (Likert, 1932) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After database lock |
Después del cierre de la base de datos |
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E.5.2 | Secondary end point(s) |
Not applicable |
No aplicable |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Not applicable |
No aplicable |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Assessment of the overall tolerability by the investigator and the patient using a 5 point Likert scale |
Evaluación de la tolerabilidad global por el investigador y el paciente mediante una escala de Likert de 5 puntos (Likert, 1932) |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Mismo producto en investigación en ambos brazos pero distinto nº iyecciones,estandar vs aceledado |
Same IMP in both arms but different number of injections, standard versus accelerated |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 | No |
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 |
Germany |
Poland |
Russian Federation |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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
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The end of the trial is defined as the database lock in order to permit the data cleaning procedure after the last visit of the last patient |
El fin del ensayo se define como el cierre de la base de datos para permitir la limpieza de datos después de la última visita del último paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |