| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hypereosinophilic Syndrome (HES) |
| sindrome ipereosinofila (HES) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hypereosinophilic Syndrome (HES) |
| sindrome ipereosinofila (HES) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| 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 | 10048643 |
| E.1.2 | Term | Hypereosinophilic syndrome |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the effect of benralizumab on the time to first HES worsening/flare |
| Valutare l’effetto di benralizumab sul tempo che precede il primo evento di peggioramento/riacutizzazione della HES |
|
| E.2.2 | Secondary objectives of the trial |
For DB period to evaluate the effect of benralizumab on:
-time to 1st haematological relapse
-proportion of patients (1) who experience HES worsening/flare (2) with
haematologic relapse and (3) who maintain absolute eosinophil count (AEC) <500 cells/µL for 24 weeks
-corticosteroid use
-patient-reported measure of fatigue
-health status and related quality of life measures (HRQoL): SF-36v2, PGIS, PGIC
And also the safety, tolerability, PK and immunogenicity of benralizumab in patients with HES
For OLE extension period to evaluate the effect of benralizumab on:
-proportion of patients who experience HES worsening/flare and on the number of HES worsening/flare (a)
-patient reported measure of fatigue (b)
-HRQoL (b) |
Periodo di trattamento in doppio cieco
- Valutare l’effetto di benralizumab sul tempo che precede la prima recidiva ematologica
- Valutare l’effetto di benralizumab sul numero di pazienti che mantiene un’AEC <500 cellule/µl per 24 settimane
- Valutare l’effetto di benralizumab sull’utilizzo di corticosteroidi
- Valutare l’effetto di benralizumab sulla misura dell’affaticamento riferito dal paziente
- Valutare l’effetto di benralizumab sulle misure dello stato di salute/qualità della vita correlata alla salute (HRQoL): SF-36v2, PGIS, PGIC
- Valutare la farmacocinetica (PK) e l’immunogenicità di benralizumab in pazienti affetti da HES
Periodo di trattamento con estensione in aperto
- Valutare l’effetto di benralizumab sulla percentuale di pazienti che manifesta un peggioramento/una riacutizzazione della HES
- Valutare l’effetto di benralizumab sulla misura dell’affaticamento riferito dal paziente
- Valutare l’effetto di benralizumab sulla HRQoL (b) |
|
| 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: Mechanistic sub-study (Protocol v.5.0 dd 06Aug202): To support identifying predictors and mechanisms of response to benralizumab in adults. The additional exploratory analyses will be performed from three whole blood samples:
- for DNA analysis to determine clinical subtype of HES by targeted PCR (all study sites).
- for more in-depth phenotyping of lymphocytes and other leukocytes by flow cytometry of peripheral blood mononuclear cells (PBMC) (all study sites).
- for phenotyping of eosinophils by flow cytometry (only selected mechanistic sub-study sites)
Patient qualitative interview sub-study: to characterise the impact of HES on patients´lives and their experiences with the study treatment (selected sites only).
|
Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Mechanistic sub-study (Protocol v.5.0 dd 06Aug202) : To support identifying predictors and mechanisms of response to benralizumab in adults. The additional exploratory analyses will be performed from three whole blood samples:
- for DNA analysis to determine clinical subtype of HES by targeted PCR (all study sites).
- for more in-depth phenotyping of lymphocytes and other leukocytes by flow cytometry of peripheral blood mononuclear cells (PBMC) (all study sites).
- for phenotyping of eosinophils by flow cytometry (only selected mechanistic sub-study sites)
Patient qualitative interview sub-study: to characterise the impact of HES on patients´lives and their experiences with the study treatment (selected sites only).
|
|
| E.3 | Principal inclusion criteria |
1. Provision of the signed and dated written informed consent of the patient or the patient's legally authorised representative, and informed assent from the patient (per local regulations) prior to any mandatory study-specific procedures, sampling, and analyses
2. Males and females 12 years of age and older at the time of signing the ICF
3. Documented diagnosis of HES (history of persistent eosinophilia >1500 cells/µL without secondary cause on 2 examinations [interval =1 month; Valent et al 2012] and evidence of end organ manifestations attributable to the eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
5. Stable HES treatment dose(s) and regimen for for =4 weeks at the time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative of HES worsening/flare (other than isolated
eosinophilia) at Visit 1
7. AEC =1000 cells/µL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC <1000 cells/µL after a 2-day course of OCS 1 mg/kg/day at Visit 2 (assessed by local laboratory)
9. Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the Investigator) from enrolment, throughout the study duration, and within 12 weeks after last dose of IP and have a negative urine dipstick pregnancy test result on Visit 1
10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for =12 months prior to the planned date of enrolment without an alternative medical cause |
1. Provision of the signed and dated written informed consent of the patient or the patient's legally authorised representative, and informed assent from the patient (per local regulations) prior to any mandatory study-specific procedures, sampling, and analyses
2. Males and females 12 years of age and older at the time of signing the ICF
3. Documented diagnosis of HES (history of persistent eosinophilia >1500 cells/µL without secondary cause on 2 examinations [interval =1 month; Valent et al 2012] and evidence of end organ manifestations attributable to the eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
5. Stable HES treatment dose(s) and regimen for for =4 weeks at the time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative of HES worsening/flare (other than isolated
eosinophilia) at Visit 1
7. AEC =1000 cells/µL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC <1000 cells/µL after a 2-day course of OCS 1 mg/kg/day at Visit 2 (assessed by local laboratory)
9. Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the Investigator) from enrolment, throughout the study duration, and within 12 weeks after last dose of IP and have a negative urine dipstick pregnancy test result on Visit 1
10. Women not of childbearing potential are defined as women who are either permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for =12 months prior to the planned date of enrolment without an alternative medical cause |
|
| E.4 | Principal exclusion criteria |
1. Life-threatening HES and/or HES complication(s) as judged by the Investigator:
(a) Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization, (b) History of thrombotic complications, stroke, or significant cardiac damage related to HES, if the respective events were life threatening and currently represent a risk of life-threatening disease complications. Events that occurred in the past but considered resolved or stable, can be accepted if, as per Investigator's judgment participation in the study will not put the patient at risk c) Disease severity that, in the opinion of the Investigator, makes the patient inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment which, in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete the entire duration of the study
5.Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant cardiac damage, clinically significant echocardiography (if available) or ECG findings within 12 months prior to Visit 1 or clinically significant ECG findings at screening that, in the opinion of the Investigator, may put the patients at risk.
7. Known currently active liver disease
(a) Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen or hepatitis C antibody) or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis
(b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level =3× the upper limit of normal (ULN) during the screening period (AST or ALT >5×ULN if documented HES with liver manifestations).
Transient increase of AST/ALT level that resolves by the time of randomisation is acceptable if, in the Investigator's opinion, the patient does not have an active liver disease and meets other eligibility criteria
8. Current malignancy, or history of malignancy, except:
(a) Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to the date that informed consent, and assent when applicable, was obtained
(b) Patients who have had other malignancies are eligible provided the patient is in remission and curative therapy was completed at least 5
years prior to the date informed consent, and assent when applicable, was obtained
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as well as clinically significant viral, bacterial, or fungal infection within 4
weeks prior to Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not been treated or has failed to respond to standard of care therapy. A confirmation of a complete resolution of any helminth parasitic infection prior to Visit 1 should be available
12. A history of known immunodeficiency disorder other than that explained by the use of
OCS or other therapy taken for HES. Positive human immunodeficiency virus (HIV) test.
[...] |
1. Life-threatening HES and/or HES complication(s) as judged by the Investigator:
(a) Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomization, (b) History of thrombotic complications, stroke, or significant cardiac damage related to HES, if the respective events were life threatening and currently represent a risk of life-threatening disease complications. Events that occurred in the past but considered resolved or stable, can be accepted if, as per Investigator's judgment participation in the study will not put the patient at risk c) Disease severity that, in the opinion of the Investigator, makes the patient inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory, or any other system abnormalities that are not associated with HES and are uncontrolled with standard treatment which, in the opinion of the Investigator, may put the patient at risk because of his/her participation in the study, or may influence the results of the study, or the patient's ability to complete the entire duration of the study
5.Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant cardiac damage, clinically significant echocardiography (if available) or ECG findings within 12 months prior to Visit 1 or clinically significant ECG findings at screening that, in the opinion of the Investigator, may put the patients at risk.
7. Known currently active liver disease
(a) Chronic stable hepatitis B and C (including positive testing for hepatitis B surface antigen or hepatitis C antibody) or other stable chronic liver disease are acceptable if patient otherwise meets eligibility criteria. Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice, or cirrhosis
(b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level =3× the upper limit of normal (ULN) during the screening period (AST or ALT >5×ULN if documented HES with liver manifestations).
Transient increase of AST/ALT level that resolves by the time of randomisation is acceptable if, in the Investigator's opinion, the patient does not have an active liver disease and meets other eligibility criteria
8. Current malignancy, or history of malignancy, except:
(a) Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to the date that informed consent, and assent when applicable, was obtained
(b) Patients who have had other malignancies are eligible provided the patient is in remission and curative therapy was completed at least 5
years prior to the date informed consent, and assent when applicable, was obtained
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as well as clinically significant viral, bacterial, or fungal infection within 4
weeks prior to Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has not been treated or has failed to respond to standard of care therapy. A confirmation of a complete resolution of any helminth parasitic infection prior to Visit 1 should be available
12. A history of known immunodeficiency disorder other than that explained by the use of
OCS or other therapy taken for HES. Positive human immunodeficiency virus (HIV) test.
[...] |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Time to first HES worsening/flare (HES worsening/flare: HES clinical manifestations or lab abnormalities that result in an increase/burst of oral corticosteroids (OCS) =10 mg/day for at least 2 days OR an increase, or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalization) |
| Peggioramento/riacutizzazione della HES: manifestazioni cliniche o anomalie di laboratorio della HES determinanti un aumento/un’improvvisa manifestazione di OCS =10 mg/giorno per almeno 2 giorni, OPPURE un aumento o l’aggiunta di una nuova terapia citotossica e/o immunosoppressiva, OPPURE il ricovero in ospedale |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Throughout the 24wk double-blind treatment period |
| per il periodo di trattamento in DB di 24 settimane |
|
| E.5.2 | Secondary end point(s) |
DB treatment period
-Time to first haematologic relapse
-Proportion of patients who experience HES worsening/flare
-Proportion of patients who have haematologic relapse
-Proportion of patients who have AEC<500 cells/µL for 24 weeks
-Proportion of patients who require an increase in corticosteroid dose
from baseline at any point in the double-blind treatment period
-Fatigue questionnaire
-Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralising antibodies (nAb)
-Safety and tolerability will be evaluated in terms of adverse events (AEs), vital signs, clinical laboratory, and electrocardiogram (ECG) OLE treatment period
-Proportion of patients who experience HES worsening/flare
-Annualized rate of HES worsening/flare
-Fatigue questionnaire
-Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory, and ECG
-Serum benralizumab concentrations, anti-benralizumab antibodies and nAb
-HES symptom questionnaire
-HRQoL |
DB treatment period
-Time to first haematologic relapse
-Proportion of patients who experience HES worsening/flare
-Proportion of patients who have haematologic relapse
-Proportion of patients who have AEC<500 cells/µL for 24 weeks
-Proportion of patients who require an increase in corticosteroid dose
from baseline at any point in the double-blind treatment period
-Fatigue questionnaire
-Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralising antibodies (nAb)
-Safety and tolerability will be evaluated in terms of adverse events (AEs), vital signs, clinical laboratory, and electrocardiogram (ECG) OLE treatment period
-Proportion of patients who experience HES worsening/flare
-Annualized rate of HES worsening/flare
-Fatigue questionnaire
-Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory, and ECG
-Serum benralizumab concentrations, anti-benralizumab antibodies and nAb
-HES symptom questionnaire
-HRQoL |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Varies depending on the endpoint/objective |
| Varies depending on the endpoint/objective |
|
| 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 | Yes |
| 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 | No |
| 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 | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Israel |
| Japan |
| United States |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Poland |
| Switzerland |
|
| 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 study is defined as the last expected visit/contact of the last patient undergoing the study. |
| The end of study is defined as the last expected visit/contact of the last patient undergoing the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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