| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe uncontrolled asthma |
| severe uncontrolled asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occurring despite the use of other available treatments |
| Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occurring despite the use of other available treatments |
|
| 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 | 10049106 |
| E.1.2 | Term | Asthma chronic |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
| To determine the effect of benralizumab on the rate of asthma exacerbations |
| To determine the effect of benralizumab on the rate of asthma exacerbations |
|
| E.2.2 | Secondary objectives of the trial |
To determine the effect of benralizumab on:
- patient-reported disease-specific quality of life.
- lung function.
- patient-reported asthma control.
- time to first asthma exacerbation.
- lung function at home.
- general quality of life and health status.
To evaluate patient impression of overall asthma severity and change in the overall asthma status.
To determine the effect of benralizumab on the patient's predominant symptoms and disease specific health-related quality of life in patients
with doctor diagnosed chronic sinusitis with nasal polyposis.
Safety Objective: To assess the safety and tolerability of benralizumab Exploratory Objectives:
To determine the effect of:
-eosinophil depletion with benralizumab on Biomarker components of known asthma inflammatory pathways or airway remodeling and Biomarker surrogates of eosinophilic inflammation/activation -benralizumab on the patient's level of asthma control based standard asthma guidance recommendations |
To determine the effect of benralizumab on:
- patient-reported disease-specific quality of life.
- lung function.
- patient-reported asthma control.
- time to first asthma exacerbation.
- lung function at home.
- general quality of life and health status.
To evaluate patient impression of overall asthma severity and change in the overall asthma status.
To determine the effect of benralizumab on the patient's predominant symptoms and disease specific health-related quality of life in patients
with doctor diagnosed chronic sinusitis with nasal polyposis.
Safety Objective: To assess the safety and tolerability of benralizumab Exploratory Objectives:
To determine the effect of:
-eosinophil depletion with benralizumab on Biomarker components of known asthma inflammatory pathways or airway remodeling and Biomarker surrogates of eosinophilic inflammation/activation -benralizumab on the patient's level of asthma control based standard asthma guidance recommendations |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Other types of substudies
Specify title, date and version of each substudy with relative objectives: Main objective: To assess the potential for benralizumab treated patients
to reduce their standard of care asthma controller regimen while
maintaining asthma control.
Endpoint: Number of adapted GINA step category changes from Visit 15
to the EOS Visit 27 (Day 560/Week 80).
Other Objectives: To assess standard asthma efficacy measures for
benralizumab treated patients who reduce their standard of care asthma
controller regimen.
Endpoints:
-Change in continuous asthma efficacy measures (including ACQ6 and
SGRQ) from Visit 15 to the EOS Visit 27 (Day 560/Week 80).
-Change in continuous asthma efficacy measures (including ACQ6 and
SGRQ) from Visit 4 to the EOS Visit 27 (Day 560/Week 80).
-Clinically significant asthma exacerbations from Visit 15 to the EOS Visit
27.
Safety Objective: To assess the safety and tolerability of benralizumab
during treatment period.
Endpoint: AEs, physical examination, vital signs during the open label
benralizumab treatment period (Visit 13 to Visit 27).
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Main objective: To assess the potential for benralizumab treated patients
to reduce their standard of care asthma controller regimen while
maintaining asthma control.
Endpoint: Number of adapted GINA step category changes from Visit 15
to the EOS Visit 27 (Day 560/Week 80).
Other Objectives: To assess standard asthma efficacy measures for
benralizumab treated patients who reduce their standard of care asthma
controller regimen.
Endpoints:
-Change in continuous asthma efficacy measures (including ACQ6 and
SGRQ) from Visit 15 to the EOS Visit 27 (Day 560/Week 80).
-Change in continuous asthma efficacy measures (including ACQ6 and
SGRQ) from Visit 4 to the EOS Visit 27 (Day 560/Week 80).
-Clinically significant asthma exacerbations from Visit 15 to the EOS Visit
27.
Safety Objective: To assess the safety and tolerability of benralizumab
during treatment period.
Endpoint: AEs, physical examination, vital signs during the open label
benralizumab treatment period (Visit 13 to Visit 27).
|
|
| E.3 | Principal inclusion criteria |
1.Written informed consent for study participation must be obtained prior to any study related procedures being performed and according to international guidelines and/or applicable European Union (EU) guidelines.
2.Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a history of physician-diagnosed asthma
requiring treatment with medium-to-high dose ICS plus asthma controller, for at least 12 months prior to Visit 1. Other acceptable
asthma controllers include a long acting bronchodilator (LABA or long-acting muscarinic antagonists [LAMA]), a leukotriene
inhibitor, theophylline preparations or maintenance OCS (daily or every other day OCS requirement in order to maintain asthma
control; maximum total daily dose 20 mg prednisone or equivalent).
3.Documented current treatment with high daily doses of ICS plus at least one other asthma controller for at least 3 months prior
to Visit 1; see inclusion criterion 2 for acceptable other asthma controllers.
For ICS/LABA combination preparations, highest-strength maintenance doses approved in the given country will meet this criterion.
If the ICS and the other asthma controller therapies are given by separate inhalers, then the patient must be on a high daily ICS
dose.
4.History of at least 2 asthma exacerbations while on ICS plus another asthma controller (see inclusion criterion 2 for examples)
that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12 months prior to Visit 1. For patients receiving
corticosteroids as a maintenance therapy, the corticosteroid treatment for the exacerbation is defined as a temporary increase of
their maintenance dose.
5.ACQ6 score =1.5 at Visit 1.
6.Screening pre-bronchodilator (pre-BD) FEV1 of <80% predicted at Visit 2
Note: Spirometry testing should only be performed if the patient meets the asthma medication hold for lung function testing (see
Section 3.10.2), the test should be postponed to another day prior to Visit 3 to improve the chances of achieving a qualifying FEV1
that is not affected by bronchodilator medication.
7.Evidence of asthma as documented by airway reversibility (FEV1 =12%) demonstrated at Visit 2 or Visit 3.
8.Peripheral blood eosinophil count of =300 cells/µL assessed by central laboratory at Visit 1 or Visit 2.
Per la lista completa vedere il protocollo |
1. Il consenso informato scritto per la partecipazione allo studio deve essere ottenuto prima che vengano eseguite le procedure relative allo studio e secondo le linee guida internazionali e / o le linee guida dell'Unione Europea (UE) applicabili.
2. pazienti donna o uomo di età tra 18 e 75 anni inclusi al momento della visita 1 con una storia di asma diagnosticata dal medico che richiedono un trattamento con ICS a dose medio-alta più controllore dell'asma, per almeno 12 mesi prima della visita 1. Accettabile anche: i controllori di asma includono un broncodilatatore a lunga durata d'azione, un leucotriene
inibitore, preparazioni di teofillina o OCS di mantenimento (fabbisogno giornaliero o giornaliero di OCS per mantenere l'asma controllo; dose massima giornaliera totale di 20 mg di prednisone o equivalente).
3. Trattamento corrente documentato con alte dosi giornaliere di ICS più almeno un altro controller di asma per almeno 3 mesi prima
della visita 1. Per le preparazioni combinate ICS / LABA, le dosi di mantenimento ad alta resistenza approvate nel paese indicato soddisfano questo criterio.
Se l'ICS e le altre terapie per il controllo dell'asma sono fornite da inalatori separati, il paziente deve essere sottoposto a un ICS giornaliero di dose elevata
4. Storia di almeno 2 riacutizzazioni dell'asma mentre su ICS più un altro controllore di asma (vedere il criterio di inclusione 2 per gli esempi)
che richiedeva un trattamento con corticosteroidi sistemici (IM, IV o orale) nei 12 mesi precedenti la visita 1. Per i pazienti che ricevevano
corticosteroidi come terapia di mantenimento, il trattamento con corticosteroidi per l'esacerbazione è definito come un aumento temporaneo di
la loro dose di mantenimento.
5. Punteggio ACQ6 = 1,5 alla Visita 1.
6.Screening pre-broncodilatatore (pre-BD) FEV1 <80% previsto alla visita 2
Nota: il test spirometrico deve essere eseguito solo se il paziente incontra la sospensione del farmaco per l'asma per il test di funzionalità polmonare (vedere
Sezione 3.10.2), il test deve essere posticipato a un altro giorno prima di Visit 3 per migliorare le possibilità di raggiungere un FEV1 qualificante
questo non è influenzato dai farmaci broncodilatatori.
7. Evidenza di asma documentata dalla reversibilità delle vie aeree (FEV1 =12%) dimostrata alla Visita 2 o Visita 3.
8. Conteggio degli eosinofili periferici di =300 cellule / µL valutato dal laboratorio centrale alla Visita 1 o Visita 2.
Per la lista completa vedere il protocollo |
|
| E.4 | Principal exclusion criteria |
1. Malattia polmonare clinicamente importante diversa dall'asma o diagnosticata con malattia polmonare o sistemica, diversa dall'asma a cui sono associati elevati eosinofili periferici
2. infezioni respiratorie superiori o inferiori entro 30 giorni prima della data in cui è stato ottenuto il consenso informato o durante il periodo di screening / run-in.
3. Qualsiasi disturbo che secondo il PI: influenza la sicurezza del paziente durante lo studio, influenza i risultati degli studi e interpretazioni, impedisce al paziente di completare lo studio
4. Storia nota di allergia o reazione a qualsiasi componente della formulazione IP.
5. infezione parassitaria diagnosticata entro 24 settimane prima del consenso informato, non trattata o che non ha risposto a terapia standard
6. Eventuali risultati anormali clinicamente significativi nell'esame fisico, segni vitali, ematologia o chimica clinica durante il periodo di screening
7. malattia cardiaca significativa o anomalia ECG ottenuta durante lo screening / run-in
periodo può mettere a rischio il paziente o interferire con le valutazioni dello studio.
8. Storia di abuso di alcol o droghe nei 12 mesi precedenti alla data di acquisizione del consenso informato.
9. storia di un noto disturbo di HIV
10. Fumatori in corso o ex fumatori con una storia di fumo =10 anni . Un ex fumatore è definito come un paziente che ha smesso fumare a almeno 6 mesi prima della visita 1.
11. Malignità corrente o storia di neoplasia, fatta eccezione per:
I pazienti che hanno avuto tumori cutanei non-melanoma o carcinoma in situ della cervice sono ammissibili a condizione che il paziente sia remissione e la terapia curativa è stata completata almeno 12 mesi prima della data in cui è stato ottenuto il consenso informato.
I pazienti che hanno avuto altre neoplasie sono eleggibili a condizione che il paziente sia in remissione e che la terapia sia curativa completata almeno 5 anni prima della data di acquisizione del consenso informato.
12. Uso approvato o off-label di immunosoppressivi sistemici entro 3 mesi prima della data del consenso informato. Questi includono ma non sono limitati a piccole molecole: metotrexato, ciclosporina, azatioprina e immunosoppressivi / immunomodulanti biologici come bloccanti del TNF. Uso regolare di corticosteroidi orali, sono esclusi, tranne che per l'indicazione di asma.
13. Non sono consentiti prodotti concorrenti per l'asma, ad eccezione dell'immunoterapia allergica stabile (definita come una dose stabile e
regime al momento della visita 1). Periodi di washout accettabili per altri farmaci biologici per l'asma:
Altri prodotti per l'abbassamento di eosinofili indicati per l'asma (incluso
mepolizumab o reslizumab): almeno 4 mesi. Uso preuso di omalizumab: almeno 1 mese.
14. ricezione precedente di benralizumab (MEDI-563).
15. Ricevimento di qualsiasi farmaco sperimentale come parte di uno studio di ricerca entro circa 5 emivite prima della randomizzazione.
Per la lista completa vedere il protocollo |
1.Clinically important pulmonary disease other than asthma or ever been
diagnosed with pulmonary or systemic disease, other than asthma, that
are associated with elevated peripheral eosinophil counts
2.Acute upper or lower respiratory infections within 30 days prior to the date informed consent is obtained or during the screening/run-in period.
3.Any disorder that is not stable in the opinion of the Investigator and could: Affect the safety of the patient throughout the study. Influence the findings of the studies or their interpretations.
Impede the patient's ability to complete the entire duration of study.
4.Known history of allergy or reaction to any component of the IP formulation.
5.A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been
treated with, or has failed to respond to, standard of care therapy.
6.Any clinically significant abnormal findings in physical examination, vital signs, hematology, or clinical chemistry during screening period
7.Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality obtained during the screening/run-in
period, which in
the opinion of the Investigator may put the patient at risk or interfere with study assessments.
8.History of alcohol or drug abuse within 12 months prior to the date informed consent is obtained.
9.A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
10.Current smokers or former smokers with a smoking history of =10 pack years. A former smoker is defined as a patient who quit
smoking at
least 6 months prior to Visit 1.
11.Current malignancy, or history of malignancy, except for:
Patients who have had non-melanoma skin cancers or in situ carcinoma of the cervix are eligible provided that the patient is in
remission and
curative therapy was completed at least 12 months prior to the date informed consent is obtained.
Patients who have had other malignancies are eligible provided that the patient is in remission and curative therapy was
completed at least 5
years prior to the date informed consent is obtained.
12.Approved or off-label use of systemic immunosuppressive
medications within 3 months prior to the date informed consent is obtained. These include but are not limited to small molecules
such as
methotrexate, cyclosporine, azathioprine, and
immunosuppressive/immunomodulating biologics such as tumor necrosis factor (TNF) blockers. Regular use of systemic (oral)
corticosteroids is also excluded except for the indication of asthma.
13.Concurrent biologics for asthma are not allowed except for stable allergen immunotherapy (defined as a stable dose and
regimen at the time of Visit 1). Acceptable washout periods for other asthma biologics:
Other eosinophil lowering products indicated for asthma (including
mepolizumab or reslizumab): at least 4 months.Prior omalizumab use: at least 1 month.
14.Previously received benralizumab (MEDI-563).
15.Receipt of any investigational medication as part of a research study within approximately 5 half-lives prior to randomization.
Per la lista completa vedere il protocollo |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The annualized rate of asthma exacerbations between benralizumab and placebo. |
| The annualized rate of asthma exacerbations between benralizumab and placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Treatment period of 24 weeks. |
| Treatment period of 24 weeks. |
|
| E.5.2 | Secondary end point(s) |
The change from baseline (Visit 4) in Saint George Respiratory Questionnaire (SGRQ) to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) in forced expiratory volume in first second (FEV1) over the treatment period (up to and including Day 168/Week 24).
The change from baseline (Visit 4) in Asthma Control Questionnaire 6 (ACQ6) to the EOT (Day 168/Week 24).
Time to first asthma exacerbation (treatment period 24 weeks).
The change from run-in baseline morning peak expiratory flow (PEF) to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) SF 36v2 to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) in PGI-S to the EOT (Day 168/Week 24).
The degree of change reported by the patient (PGI-C) and Investigator (CGI-C) expressed as a proportion of each of the 7 possible responses to the EOT (Day 168/Week 24). The degree of change reported by the patient in their predominant
symptom to the EOT (Day 168/Week 24).
The change from baseline (Visit 3) in the sino-nasal outcome test (SNOT-22) score to the EOT (Day 168/Week 24).
Safety: Adverse events (AEs), laboratory variables, physical examination.
Exploratory:
The change from baseline (Visit 4) in circulating biomarkers to each prespecified scheduled assessment during the treatment period.
The proportion of time that that the patient's asthma is well-controlled based on composite diary measures. |
The change from baseline (Visit 4) in Saint George Respiratory Questionnaire (SGRQ) to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) in forced expiratory volume in first second (FEV1) over the treatment period (up to and including Day 168/Week 24).
The change from baseline (Visit 4) in Asthma Control Questionnaire 6 (ACQ6) to the EOT (Day 168/Week 24).
Time to first asthma exacerbation (treatment period 24 weeks).
The change from run-in baseline morning peak expiratory flow (PEF) to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) SF 36v2 to the EOT (Day 168/Week 24).
The change from baseline (Visit 4) in PGI-S to the EOT (Day 168/Week 24).
The degree of change reported by the patient (PGI-C) and Investigator (CGI-C) expressed as a proportion of each of the 7 possible responses to the EOT (Day 168/Week 24). The degree of change reported by the patient in their predominant
symptom to the EOT (Day 168/Week 24).
The change from baseline (Visit 3) in the sino-nasal outcome test (SNOT-22) score to the EOT (Day 168/Week 24).
Safety: Adverse events (AEs), laboratory variables, physical examination.
Exploratory:
The change from baseline (Visit 4) in circulating biomarkers to each prespecified scheduled assessment during the treatment period.
The proportion of time that that the patient's asthma is well-controlled based on composite diary measures. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
From Baseline (Visit 4) to EOT (Day 168/ Week 24).
Throughout 24 week treatment period. |
From Baseline (Visit 4) to EOT (Day 168/ Week 24).
Throughout 24 week treatment period. |
|
| 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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
| Exploratory Biomarkers. |
| Exploratory Biomarkers. |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Double blind for 24 week period. Patients can then be enrolled in 56 week open label sub study. |
| Double blind for 24 week period. Patients can then be enrolled in 56 week open label sub study. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 22 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 118 |
| 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 | Information not present in EudraCT |
| 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 |
| Australia |
| Canada |
| United States |
| Austria |
| Belgium |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
|
| 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
|
| The last visit of the last patient undergoing the study. The final study visit will be the telephone FU Visit. |
| The last visit of the last patient undergoing the study. The final study visit will be the telephone FU Visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
